Ketone compounds and compositions for cholesterol management and related uses

ABSTRACT

The present invention relates to novel ketone compounds, compositions comprising ketone compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising a ketone compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer&#39;s Disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

1. FIELD OF THE INVENTION

The invention encompasses ketone compounds and pharmaceuticallyacceptable salts, hydrates, solvates, and mixtures thereof; compositionscomprising urea and thiourea compounds and pharmaceutically acceptablesalts, hydrates, solvates, and mixtures thereof; and methods fortreating or preventing a disease or disorder such as, but not limitedto, aging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation,insulin resistance, lipid elimination in bile, modulating C reactiveprotein, obesity, oxysterol elimination in bile, pancreatitis,Parkinson's disease, a peroxisome proliferator activatedreceptor-associated disorder, phospholipid elimination in bile, renaldisease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), athrombotic disorder, or enhancing bile production, or enhancing reverselipid transport, which method comprise administering a ketone compoundor composition of the invention to a patient in need thereof. Thecompounds of the invention can also treat or prevent inflammatoryprocesses and diseases like gastrointestinal disease, irritable bowelsyndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease,ulcerative colitis), arthritis (e.g., rheumatoid arthritis,osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism.

2. BACKGROUND OF THE INVENTION

Obesity, hyperlipidemia, and diabetes have been shown to play a causalrole in atherosclerotic cardiovascular diseases, which currently accountfor a considerable proportion of morbidity in Western society. Further,one human disease, termed “Syndrome X” or “Metabolic Syndrome”, ismanifested by defective glucose metabolism (insulin resistance),elevated blood pressure (hypertension), and a blood lipid imbalance(dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.

The evidence linking elevated serum cholesterol to coronary heartdisease is overwhelming. Circulating cholesterol is carried by plasmalipoproteins, which are particles of complex lipid and proteincomposition that transport lipids in the blood. Low density lipoprotein(LDL) and high density lipoprotein (HDL) are the majorcholesterol-carrier proteins. LDL is believed to be responsible for thedelivery of cholesterol from the liver, where it is synthesized orobtained from dietary sources, to extrahepatic tissues in the body. Theterm “reverse cholesterol transport” describes the transport ofcholesterol from extrahepatic tissues to the liver, where it iscatabolized and eliminated. It is believed that plasma HDL particlesplay a major role in the reverse transport process, acting as scavengersof tissue cholesterol. HDL is also responsible for the removal ofnon-cholesterol lipid, oxidized cholesterol and other oxidized productsfrom the bloodstream.

Atherosclerosis, for example, is a slowly progressive diseasecharacterized by the accumulation of cholesterol within the arterialwall. Compelling evidence supports the belief that lipids deposited inatherosclerotic lesions are derived primarily from plasma apolipoproteinB (apo B)-containing lipoproteins, which include chylomicrons, CLDL,intermediate-density lipoproteins (IDL), and LDL. The apo B-containinglipoprotein, and in particular LDL, has popularly become known as the“bad” cholesterol. In contrast, HDL serum levels correlate inverselywith coronary heart disease. Indeed, high serum levels of HDL areregarded as a negative risk factor. It is hypothesized that high levelsof plasma HDL are not only protective against coronary artery disease,but may actually induce regression of atherosclerotic plaque (e.g., seeBadimon et al., 1992, Circulation 86:(Suppl. III)86-94; Dansky andFisher, 1999, Circulation 100:1762 3.). Thus, HDL has popularly becomeknown as the “good” cholesterol.

2.1. Cholesterol Transport

The fat-transport system can be divided into two pathways: an exogenousone for cholesterol and triglycerides absorbed from the intestine and anendogenous one for cholesterol and triglycerides entering thebloodstream from the liver and other non-hepatic tissue.

In the exogenous pathway, dietary fats are packaged into lipoproteinparticles called chylomicrons, which enter the bloodstream and delivertheir triglycerides to adipose tissue for storage and to muscle foroxidation to supply energy. The remnant of the chylomicron, whichcontains cholesteryl esters, is removed from the circulation by aspecific receptor found only on liver cells. This cholesterol thenbecomes available again for cellular metabolism or for recycling toextrahepatic tissues as plasma lipoproteins.

In the endogenous pathway, the liver secretes a large, very-low-densitylipoprotein particle (VLDL) into the bloodstream. The core of VLDLconsists mostly of triglycerides synthesized in the liver, with asmaller amount of cholesteryl esters either synthesized in the liver orrecycled from chylomicrons. Two predominant proteins are displayed onthe surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoproteinE (apo E), although other apolipoproteins are present, such asapolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). WhenVLDL reaches the capillaries of adipose tissue or of muscle, itstriglyceride is extracted. This results in the formation of a new kindof particle called intermediate-density lipoprotein (IDL) or VLDLremnant, decreased in size and enriched in cholesteryl esters relativeto a VLDL, but retaining its two apoproteins.

In human beings, about half of the IDL particles are removed from thecirculation quickly, generally within two to six hours of theirformation. This is because IDL particles bind tightly to liver cells,which extract IDL cholesterol to make new VLDL and bile acids. The IDLnot taken up by the liver is catabolized by the hepatic lipase, anenzyme bound to the proteoglycan on liver cells. Apo E dissociates fromIDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.

Primarily, the liver takes up and degrades circulating cholesterol tobile acids, which are the end products of cholesterol metabolism. Theuptake of cholesterol-containing particles is mediated by LDL receptors,which are present in high concentrations on hepatocytes. The LDLreceptor binds both apo E and apo B-100 and is responsible for bindingand removing both IDL and LDL from the circulation. In addition, remnantreceptors are responsible for clearing chylomicrons and VLDL remnants(i.e., IDL). However, the affinity of apo E for the LDL receptor isgreater than that of apo B-100. As a result, the LDL particles have amuch longer circulating life span than IDL particles; LDL circulates foran average of two and a half days before binding to the LDL receptors inthe liver and other tissues. High serum levels of LDL, the “bad”cholesterol, are positively associated with coronary heart disease. Forexample, in atherosclerosis, cholesterol derived from circulating LDLaccumulates in the walls of arteries. This accumulation forms bulkyplaques that inhibit the flow of blood until a clot eventually forms,obstructing an artery and causing a heart attack or stroke.

Ultimately, the amount of intracellular cholesterol liberated from theLDL controls cellular cholesterol metabolism. The accumulation ofcellular cholesterol derived from VLDL and LDL controls three processes.First, it reduces the ability of the cell to make its own cholesterol byturning off the synthesis of HMGCoA reductase, a key enzyme in thecholesterol biosynthetic pathway. Second, the incoming LDL-derivedcholesterol promotes storage of cholesterol by the action of cholesterolacyltransferase (“ACAT”), the cellular enzyme that converts cholesterolinto cholesteryl esters that are deposited in storage droplets. Third,the accumulation of cholesterol within the cell drives a feedbackmechanism that inhibits cellular synthesis of new LDL receptors. Cells,therefore, adjust their complement of LDL receptors so that enoughcholesterol is brought in to meet their metabolic needs, withoutoverloading (for a review, see Brown & Goldstein, in The PharmacologicalBasis Of Therapeutics, 8th Ed., Goodman & Gilman, Pergamon Press, NewYork, 1990, Ch. 36, pp. 874-896).

High levels of apo B-containing lipoproteins can be trapped in thesubendothelial space of an artery and undergo oxidation. The oxidizedlipoprotein is recognized by scavenger receptors on macrophages. Bindingof oxidized lipoprotein to the scavenger receptors can enrich themacrophages with cholesterol and cholesteryl esters independently of theLDL receptor. Macrophages can also produce cholesteryl esters by theaction of ACAT. LDL can also be complexed to a high molecular weightglycoprotein called apolipoprotein(a), also known as apo(a), through adisulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) orLp(a). Elevated levels of Lp(a) are detrimental, having been associatedwith atherosclerosis, coronary heart disease, myocardial infarction,stroke, cerebral infarction, and restenosis following angioplasty.

2.2. Reverse Cholesterol Transport

Peripheral (non-hepatic) cells predominantly obtain their cholesterolfrom a combination of local synthesis and uptake of preformed sterolfrom VLDL and LDL. Cells expressing scavenger receptors, such asmacrophages and smooth muscle cells, can also obtain cholesterol fromoxidized apo B-containing lipoproteins. In contrast, reverse cholesteroltransport (RCT) is the pathway by which peripheral cell cholesterol canbe returned to the liver for recycling to extrahepatic tissues, hepaticstorage, or excretion into the intestine in bile. The RCT pathwayrepresents the only means of eliminating cholesterol from mostextrahepatic tissues and is crucial to the maintenance of the structureand function of most cells in the body.

The enzyme in blood involved in the RCT pathway, lecithin:cholesterolacyltransferase (LCAT), converts cell-derived cholesterol to cholesterylesters, which are sequestered in HDL destined for removal. LCAT isproduced mainly in the liver and circulates in plasma associated withthe HDL fraction. Cholesterol ester transfer protein (CETP) and anotherlipid transfer protein, phospholipid transfer protein (PLTP), contributeto further remodeling the circulating HDL population (see for exampleBruce et al., 1998, Annu. Rev. Nutr. 18:297 330). PLTP supplies lecithinto HDL, and CETP can move cholesteryl esters made by LCAT to otherlipoproteins, particularly apoB-containing lipoproteins, such as VLDL.HDL triglycerides can be catabolized by the extracellular hepatictriglyceride lipase, and lipoprotein cholesterol is removed by the livervia several mechanisms.

Each HDL particle contains at least one molecule, and usually two tofour molecules, of apolipoprotein A I (apo A I). Apo A I is synthesizedby the liver and small intestine as preproapolipoprotein, which issecreted as a proprotein that is rapidly cleaved to generate a maturepolypeptide having 243 amino acid residues. Apo A I consists mainly of a22 amino acid repeating segment, spaced with helix-breaking prolineresidues. Apo A I forms three types of stable structures with lipids:small, lipid-poor complexes referred to as pre-beta-1 HDL; flatteneddiscoidal particles, referred to as pre-beta-2 HDL, which contain onlypolar lipids (e.g., phospholipid and cholesterol); and sphericalparticles containing both polar and nonpolar lipids, referred to asspherical or mature HDL (HDL3 and HDL2). Most HDL in the circulatingpopulation contains both apo A I and apo A II, a second major HDLprotein. This apo A I- and apo A II-containing fraction is referred toherein as the AI/AII-HDL fraction of HDL. But the fraction of HDLcontaining only apo A I, referred to herein as the Al HDL fraction,appears to be more effective in RCT. Certain epidemiologic studiessupport the hypothesis that the AI-HDL fraction is antiartherogenic(Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al.,1997, Eur. J. Clin. Invest. 27:299-307).

Although the mechanism for cholesterol transfer from the cell surface isunknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, isthe preferred acceptor for cholesterol transferred from peripheraltissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDLfrom the cell surface rapidly appears in the discoidal pre-beta-2 HDL.PLTP may increase the rate of disc formation (Lagrost et al., 1996, J.Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCTis lacking. LCAT reacts preferentially with discoidal and spherical HDL,transferring the 2-acyl group of lecithin or phosphatidylethanolamine tothe free hydroxyl residue of fatty alcohols, particularly cholesterol,to generate cholesteryl esters (retained in the HDL) and lysolecithin.The LCAT reaction requires an apolipoprotein such as apo A I or apo A-IVas an activator. ApoA-I is one of the natural cofactors for LCAT. Theconversion of cholesterol to its HDL-sequestered ester prevents re-entryof cholesterol into the cell, resulting in the ultimate removal ofcellular cholesterol. Cholesteryl esters in the mature HDL particles ofthe AI-HDL fraction are removed by the liver and processed into bilemore effectively than those derived from the AI/AII-HDL fraction. Thismay be due, in part, to the more effective binding of AI-HDL to thehepatocyte membrane. Several HDL receptors have been identified, themost well characterized of which is the scavenger receptor class B, typeI (SR BI) (Acton et al., 1996, Science 271:518-520). The SR-BI isexpressed most abundantly in steroidogenic tissues (e.g., the adrenals),and in the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995;Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other proposedHDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J.15:161 7; Kurata et al., 1998, J. Atherosclerosis and Thrombosis 4:1127).

While there is a consensus that CETP is involved in the metabolism ofVLDL- and LDL-derived lipids, its role in RCT remains controversial.However, changes in CETP activity or its acceptors, VLDL and LDL, play arole in “remodeling” the HDL population. For example, in the absence ofCETP, the HDL becomes enlarged particles that are poorly removed fromthe circulation (for reviews on RCT and HDL, See Fielding & Fielding,1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys.Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol.17:1053-1059).

2.3. Reverse Transport of Other Lipids

HDL is not only involved in the reverse transport of cholesterol, butalso plays a role in the reverse transport of other lipids, i.e., thetransport of lipids from cells, organs, and tissues to the liver forcatabolism and excretion. Such lipids include sphingomyelin, oxidizedlipids, and lysophophatidylcholine. For example, Robins and Fasulo(1997, J. Clin. Invest. 99:380 384) have shown that HDL stimulates thetransport of plant sterol by the liver into bile secretions.

2.4. Peroxisome Proliferator Activated Receptor Pathway

Peroxisome proliferators are a structurally diverse group of compoundsthat, when administered to rodents, elicit dramatic increases in thesize and number of hepatic and renal peroxisomes, as well as concomitantincreases in the capacity of peroxisomes to metabolize fatty acids viaincreased expression of the enzymes required for the β-oxidation cycle(Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489 530; Vamecq andDraye, 1989, Essays Biochem. 24:1115 225; and Nelali et al., 1988,Cancer Res. 48:5316 5324). Chemicals included in this group are thefibrate class of hypolipidemic drugs, herbicides, and phthalateplasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1 58).Peroxisome proliferation can also be elicited by dietary orphysiological factors, such as a high fat diet and cold acclimatization.

Insight into the mechanism whereby peroxisome proliferators exert theirpleiotropic effects was provided by the identification of a member ofthe nuclear hormone receptor superfamily activated by these chemicals(Isseman and Green, 1990, Nature 347:645 650). This receptor, termedperoxisome proliferator activated receptor α (PPARα), was subsequentlyshown to be activated by a variety of medium and long chain fatty acids.PPARα activates transcription by binding to DNA sequence elements,termed peroxisome proliferator response elements (PPRE), in the form ofa heterodimer with the retinoid X receptor (RXR). RXR is activated by9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771 774;Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440 1444, Keller etal., 1993, Proc. Natl. Acad. Sci. USA 90:2160 2164; Heyman et al., 1992,Cell 68:397 406, and Levin et al., 1992, Nature 355:359 361). Since thediscovery of PPARα, additional isoforms of PPAR have been identified,e.g., PPARβ, PPARγ and PPARδ, which have similar functions and aresimilarly regulated.

PPARs have been identified in the enhancers of a number of gene-encodingproteins that regulate lipid metabolism. These proteins include thethree enzymes required for peroxisomal β-oxidation of fatty acids;apolipoprotein A-I; medium chain acyl-CoA dehydrogenase, a key enzyme inmitochondrial β-oxidation; and aP2, a lipid binding protein expressedexclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM,4:291 296; see also Staels and Auwerx, 1998, Atherosclerosis 137Suppl:S19 23). The nature of the PPAR target genes coupled with theactivation of PPARs by fatty acids and hypolipidemic drugs suggests aphysiological role for the PPARs in lipid homeostasis.

Pioglitazone, an antidiabetic compound of the thiazolidinedione class,was reported to stimulate expression of a chimeric gene containing theenhancer/promoter of the lipid binding protein aP2 upstream of thechloroamphenicol acetyl transferase reporter gene (Harris and Kletzien,1994, Mol. Pharmacol. 45:439 445). Deletion analysis led to theidentification of an approximately 30 bp region accounting forpioglitazone responsiveness. In an independent study, this 30 bpfragment was shown to contain a PPRE (Tontonoz et al., 1994, NucleicAcids Res. 22:5628 5634). Taken together, these studies suggested thepossibility that the thiazolidinediones modulate gene expression at thetranscriptional level through interactions with a PPAR and reinforce theconcept of the interrelatedness of glucose and lipid metabolism.

2.5. Current Cholesterol Management Therapies

In the past two decades or so, the segregation of cholesterolemiccompounds into HDL and LDL regulators and recognition of thedesirability of decreasing blood levels of the latter has led to thedevelopment of a number of drugs. However, many of these drugs haveundesirable side effects and/or are contraindicated in certain patients,particularly when administered in combination with other drugs.

Bile-acid-binding resins are a class of drugs that interrupt therecycling of bile acids from the intestine to the liver. Examples ofbile-acid-binding resins are cholestyramine (QUESTRAN LIGHT,Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia& Upjohn Company). When taken orally, these positively charged resinsbind to negatively charged bile acids in the intestine. Because theresins cannot be absorbed from the intestine, they are excreted,carrying the bile acids with them. The use of such resins, however, atbest only lowers serum cholesterol levels by about 20%. Moreover, theiruse is associated with gastrointestinal side-effects, includingconstipation and certain vitamin deficiencies. Moreover, since theresins bind to drugs, other oral medications must be taken at least onehour before or four to six hours subsequent to ingestion of the resin,complicating heart patients' drug regimens.

The statins are inhibitors of cholesterol synthesis. Sometimes, thestatins are used in combination therapy with bile-acid-binding resins.Lovastatin (MEVACOR, Merck & Co., Inc.), a natural product derived froma strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers SquibbCo.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterolsynthesis by inhibiting HMGCoA reductase, the key enzyme involved in thecholesterol biosynthetic pathway. Lovastatin significantly reduces serumcholesterol and LDL-serum levels. However, serum HDL levels are onlyslightly increased following lovastatin administration. The mechanism ofthe LDL-lowering effect may involve both reduction of VLDL concentrationand induction of cellular expression of LDL-receptor, leading to reducedproduction and/or increased catabolism of LDL. Side effects, includingliver and kidney dysfunction are associated with the use of these drugs.

Nicotinic acid, also known as niacin, is a water-soluble vitaminB-complex used as a dietary supplement and antihyperlipidemic agent.Niacin diminishes the production of VLDL and is effective at loweringLDL. It is used in combination with bile-acid-binding resins. Niacin canincrease HDL when administered at therapeutically effective doses;however, its usefulness is limited by serious side effects.

Fibrates are a class of lipid-lowering drugs used to treat various formsof hyperlipidemia, elevated serum triglycerides, which may also beassociated with hypercholesterolemia. Fibrates appear to reduce the VLDLfraction and modestly increase HDL; however, the effects of these drugson serum cholesterol is variable. In the United States, fibrates havebeen approved for use as antilipidemic drugs, but have not receivedapproval as hypercholesterolemia agents. For example, clofibrate(ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent thatacts to lower serum triglycerides by reducing the VLDL fraction.Although ATROMID-S may reduce serum cholesterol levels in certainpatient subpopulations, the biochemical response to the drug isvariable, and is not always possible to predict which patients willobtain favorable results. ATROMID-S has not been shown to be effectivefor prevention of coronary heart disease. The chemically andpharmacologically related drug, gemfibrozil (LOPID, Parke-Davis), is alipid regulating agent which moderately decreases serum triglyceridesand VLDL cholesterol. LOPID also increases HDL cholesterol, particularlythe HDL2 and HDL3 subfractions, as well as both the AI/AII-HDLfractions. However, the lipid response to LOPID is heterogeneous,especially among different patient populations. Moreover, whileprevention of coronary heart disease was observed in male patientsbetween the ages of 40 and 55 without history or symptoms of existingcoronary heart disease, it is not clear to what extent these findingscan be extrapolated to other patient populations (e.g., women, older andyounger males). Indeed, no efficacy was observed in patients withestablished coronary heart disease. Serious side-effects are associatedwith the use of fibrates, including toxicity; malignancy, particularlymalignancy of gastrointestinal cancer; gallbladder disease; and anincreased incidence in non-coronary mortality. These drugs are notindicated for the treatment of patients with high LDL or low HDL astheir only lipid abnormality.

Oral estrogen replacement therapy may be considered for moderatehypercholesterolemia in post-menopausal women. However, increases in HDLmay be accompanied with an increase in triglycerides. Estrogen treatmentis, of course, limited to a specific patient population, postmenopausalwomen, and is associated with serious side effects, including inductionof malignant neoplasms; gall bladder disease; thromboembolic disease;hepatic adenoma; elevated blood pressure; glucose intolerance; andhypercalcemia.

Long chain carboxylic acids, particularly long chain α,ω-dicarboxylicacids with distinctive substitution patterns, and their simplederivatives and salts, have been disclosed for treating atherosclerosis,obesity, and diabetes (See, e.g., Bisgaier et al., 1998, J. Lipid Res.39:17-30, and references cited therein; International Patent PublicationWO 98/30530; U.S. Pat. No. 4,689,344; International Patent PublicationWO 99/00116; and U.S. Pat. No. 5,756,344). However, some of thesecompounds, for example the α,ω-dicarboxylic acids substituted at theirα,α′-carbons (U.S. Pat. No. 3,773,946), while having serum triglycerideand serum cholesterol-lowering activities, have no value for treatmentof obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).

U.S. Pat. No. 4,689,344 disclosesβ,β,β′,β′-tetrasubstituted-α,ω-alkanedioic acids that are optionallysubstituted at their α,α,α′,α′-positions, and alleges that they areuseful for treating obesity, hyperlipidemia, and diabetes. According tothis reference, both triglycerides and cholesterol are loweredsignificantly by compounds such as3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344further discloses that the β,β,β′,β′-tetramethyl-alkanediols of U.S.Pat. No. 3,930,024 also are not useful for treating hypercholesterolemiaor obesity.

Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S. Pat.No. 5,756,544, α,ω-dicarboxylic acid-terminated dialkane ethers aredisclosed to have activity in lowering certain plasma lipids, includingLp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in animals,and elevating others, such as HDL-cholesterol. The compounds are alsostated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593,phosphates of dolichol, a polyprenol isolated from swine liver, arestated to be useful in regenerating liver tissue, and in treatinghyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.

U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives withanti-diabetic, hypolipidemic, and anti-hypertensive properties. However,the administration of these compounds to patients can produce sideeffects such as bone marrow depression, and both liver and cardiaccytotoxicity. Further, the compounds disclosed by U.S. Pat. No.4,287,200 stimulate weight gain in obese patients.

It is clear that none of the commercially available cholesterolmanagement drugs has a general utility in regulating lipid, lipoprotein,insulin and glucose levels in the blood. Thus, compounds that have oneor more of these utilities are clearly needed. Further, there is a clearneed to develop safer drugs that are efficacious at lowering serumcholesterol, increasing HDL serum levels, preventing coronary heartdisease, and/or treating existing disease such as atherosclerosis,obesity, diabetes, and other diseases that are affected by lipidmetabolism and/or lipid levels. There is also a clear need to developdrugs that may be used with other lipid-altering treatment regimens in asynergistic manner. There is still a further need to provide usefultherapeutic agents whose solubility and Hydrophile/Lipophile Balance(HLB) can be readily varied.

The recitation of any reference in Section 2 of this application is notan admission that the reference is available as prior art to thisapplication.

3. SUMMARY OF THE INVENTION

In one embodiment, the invention encompasses compounds of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein

-   -   (a) each occurrence of Z is independently CH₂, CH═CH, or phenyl,        wherein each occurrence of m is independently an integer ranging        from 1 to 9, but when Z is phenyl then its associated m is 1;    -   (b) G is (CH₂)_(x), CH₂CH═CHCH₂, CH═CH, CH₂-phenyl-CH₂, or        phenyl, wherein x is 2, 3, or 4;    -   (c) W¹ and W² are independently L, V,        C(R¹)(R²)—(CH₂)_(c-)(R¹)(R²)—(CH₂)_(n-)Y, or        C(R¹)(R²)—(CH₂)_(c-)V, wherein c is 1 or 2 and n is an        independent integer ranging from 0 to 4;    -   (d) R¹ and R² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,        (C₂₋C₆)alkynyl, phenyl, or benzyl or when W¹ or W² is        C(R¹)(R²)—(CH₂)_(c-)—C(R³)(R⁴)—Y, then R¹ and R² can both be H,        or R¹ and R² and the carbon to which they are both attached are        taken together to form a (C₃-C₇)cycloakyl group;    -   (e) R³ and R⁴ are independently H, OH, (C₁₋C₆)alkyl,        (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, (C₁₋C₆)alkoxy, phenyl, benzyl,        Cl, Br, CN, NO₂, or CF₃, with the proviso that when R¹ and R²        are both H, then one of R³ or R⁴ is not H or R³ and R⁴ and the        carbon to which they are both attached are taken together to        form a (C₃₋C₇)cycloakyl group;    -   (f) L is C(R¹)(R²)—CH₂)_(n-)Y;    -   (g) V is    -   (h) Y is (C₁C₆)alkyl, OH, COOH, CHO, COOR⁵, SO₃H,    -    where        -   (I) R⁵ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each occurrence of R⁶ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups; and        -   (iii) each occurrence of R⁷ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl.

Preferred compounds of formula I are those wherein:

-   -   (a) W¹ and W² are independently L, V, or C(R¹)(R²)—(CH₂)_(c-)V,        where c is 1 or2; and    -   (b) R¹ and R² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,        (C₂₋C₆)alkynyl, phenyl, or benzyl.

Other preferred compounds of formula I are those wherein W¹ is L.

Other preferred compounds of formula I are those wherein W¹ is V.

Other preferred compounds of formula I are those wherein W¹ isC(R¹)(R²)—(CH₂)_(c-)C(R³)(R⁴)—(CH₂)_(n-)Y.

Other preferred compounds of formula I are those wherein W¹ isC(R¹)(R²)—(CH₂)_(c-)V.

Other preferred compounds of formula I are those wherein W¹ and W² areindependent L groups.

Other preferred compounds of formula I are those wherein each occurrenceof Y is independently OH, COOR⁵, or COOH.

In another embodiment, the invention encompasses compounds of formulaIa:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein

-   -   (a) each occurrence of Z is independently CH₂ or CH═CH, wherein        each occurrence of m is independently an integer ranging from 1        to 9;    -   (b) G is (CH₂)_(x), CH₂CH═CHCH₂, or CH═CH, where x is 2, 3, or        4;    -   (c) W¹ and W² are independently L, V, or C(R¹)(R²)—(CH₂)_(c-)V,        where c is 1 or 2;    -   (d) each occurrence of R¹ and R² is independently (C₁₋ ₆)alkyl,        (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, benzyl, or R¹ and R² and        the carbon to which they are both attached are taken together to        form a (C₃-C₇)cycloakyl group;    -   (e) L is C(R¹)(R²)—(CH₂)_(n-)Y, where n is an independent        integer ranging from 0 to 4;    -   (f) V is    -   (g) each occurrence of Y is independently (C₁₋C₆)alkyl, OH,        COOH, CHO, (CH₂)_(n)COOR³, SO₃H,    -    where        -   (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each occurrence of R⁴ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups; and        -   (iii) each occurrence of R⁵ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl.

Preferably, in formula Ia each occurrence of Y is independently(C₁₋C₆)alkyl, OH, COOR³, or COOH.

In yet another embodiment, the invention encompasses compounds formulaIb

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein:

-   -   (a) each occurrence of m is independently an integer ranging        from 1 to 9;    -   (b) x is 2, 3, or 4;    -   (c) n is an independent integer ranging from 0 to 4;    -   (d) each occurrence of R¹ and R² is independently (C₁₋C₆)alkyl,        (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, benzyl, or R¹ and R² and        the carbon to which they are both attached are taken together to        form a (C₃₋C₇)cycloakyl group;    -   (e) each occurrence of R¹¹ and R¹² is independently H,        (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, benzyl, or        R¹¹ and R¹² and the carbon to which they are both attached are        taken together to form a (C₃₋C₇)cycloakyl group;    -   (f) each occurrence of Y is independently (C₁₋C₆)alkyl, OH,        COOH, CHO, COOR³, SO₃H,    -    where        -   (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each occurrence of R⁴ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups; and        -   (iii) each occurrence of R⁵ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl.

Preferably in formula Ib, each occurrence of Y is independently OH,COOR³, or COOH.

In still another embodiment, the invention encompasses compounds offormula Ic

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein:

-   -   (a) each occurrence of m is an independent integer ranging from        1 to 9;    -   (b) x is 2, 3, or 4;    -   (c) V is

In another embodiment, the invention encompasses compounds of formulaII:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein

-   -   (a) R¹ and R² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,        (C₂₋C₆)alkynyl, phenyl, or benzyl; or R¹, R², and the carbon to        which they are both attached are taken together to form a        (C₃₋C₇)cycloalkyl group;    -   (b) R¹¹ and R¹² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,        (C₂₋C₆)alkynyl, phenyl, or benzyl; or R¹¹, R¹², and the carbon        to which they are both attached are taken together to form a        (C₃₋C₇)cycloalkyl group;    -   (c) n is an integer ranging from 1 to 5;    -   (d) each occurrence of m is independently an integer ranging        from 0 to 4;    -   (e) W¹ and W² are independently (C₁₋C₆)alkyl, CH₂OH, C(O)OH,        CHO, OC(O)R³, C(O)OR³, SO₃H,    -    where        -   (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each ocurrence of R⁴ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl, and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups; and        -   (iii) each occurrence of R⁵ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl.

Preferred compounds of formula II are those wherein each occurrence of Wis independently OH, COOR³, or COOH.

Other preferred compounds of formula II are those wherein R¹ and R² areindependent (C₁₋C₆)alkyl groups.

Other preferred compounds of formula II are those wherein m is 0.

Other preferred compounds of formula II are those wherein m is 1.

Other preferred compounds of formula II are those wherein R¹ and R² areeach independently (C₁₋C₆)alkyl.

Other preferred compounds of formula II are those wherein R¹ and R² areeach methyl.

Other preferred compounds of formula II are those wherein W¹ and/or W²is C(O)OH or CH₂OH.

In another embodiment, the invention encompasses compounds of formulaIIa:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein

-   -   (a) R¹ and R² are OH, COOH, CHO, COOR⁷, SO₃H,    -    where        -   (I) R⁷ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each occurrence of R⁸ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups,        -   (iii) each occurrence of R⁹ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl;    -   (b) R³ and R⁴ are (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,        phenyl, or benzyl;    -   (c) R⁵ and R⁶ are hydrogen, halogen, (C₁₋C₄)alkyl,        (C₁₋C₄)alkoxy, (C6)aryloxy, CN, or NO₂, N(R⁵)₂ where R⁵ is H,        (C₁₋C₄)alkyl, phenyl, or benzyl;    -   (d) each occurrence of m is independently an integer ranging        from 1 to 5;    -   (e) each occurrence of n is independently an integer ranging        from 0 to 4; and    -   (f) *¹ and *² represent independent chiral-carbon centers,        wherein each center may independently be R or S.

Preferred compounds of formula Ia are those wherein each occurrence ofR¹ and R² is independently OH, COOR⁷, or COOH.

Other preferred compounds of formula IIa are those wherein m is 0.

Other preferred compounds of formula IIa are those wherein m is 1.

Other preferred compounds of formula IIa are those wherein R¹ and/or R²is C(O)OH or CH₂OH.

Other preferred compounds of formula IIa are those wherein R³ and R⁴ areeach independently (C₁₋C₆)alkyl.

Other preferred compounds of formula IIa are those wherein R³ and R⁴ areeach methyl.

Other preferred compounds of formula IIa are those wherein *¹ is of thestereochemical configuration R or substantially R.

Other preferred compounds of formula IIa are those wherein *¹ is of thestereochemical configuration S or substantially S.

Other preferred compounds of formula IIa are those wherein *² is of thestereochemical configuration R or substantially R.

Other preferred compounds of formula IIa are those wherein *² is of thestereochemical configuration S or substantially S.

In a particular embodiment, compounds of formula IIa are those wherein*¹ *² are of the stereochemical configuration (S¹,S²) or substantially(S¹,S²).

In another particular embodiment, compounds of formula IIa are thosewherein *¹ *² are of the stereochemical configuration (S¹,R²) orsubstantially (S¹,R²).

In another particular embodiment, compounds of formula IIa are thosewherein *¹ *² are of the stereochemical configuration (R,R²) orsubstantially (R¹ ,R²).

In another particular embodiment, compounds of formula IIa are thosewherein *¹ *² are of the stereochemical configuration (R¹,S²) orsubstantially (R¹,S²).

In still another embodiment, the invention encompasses compounds offormula III:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein

-   -   (a) each occurrence of Z is independently CH₂, CH═CH, or phenyl,        where each occurrence of m is independently an integer ranging        from 1 to 5, but when Z is phenyl then its associated m is 1;    -   (b) G is (CH₂)_(x), CH₂CH═CHCH₂, CH═CH, CH₂-phenyl-CH₂, or        phenyl, where x is an integer ranging from 1 to 4;    -   (c) W¹ and W² are independently C(R¹)(R²)—(CH₂)_(n-)Y where n is        an integer ranging from 0 to 4;    -   (d) R¹ and R² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,        (C₂₋C₆)alkynyl, phenyl, or benzyl or R¹ and R² are both H, or        R¹, R¹, and the carbon to which they are both attached are taken        together to form a (C₃₋C₇)cycloalkyl group;    -   (e) Y is (C₁₋C₆)alkyl, (CH₂)_(n)OH, (CH₂)_(n)COOH, (CH₂)_(n)CHO,        (CH₂)_(n)COOR³, SO₃H,    -    where        -   (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,            phenyl, or benzyl and is unsubstituted or substituted with            one or more halo, OH, (C₁₋C₆)alkoxy, or phenyl groups,        -   (ii) each occurrence of R⁴ is independently H, (C₁₋C₆)alkyl,            (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and is unsubstituted or            substituted with one or two halo, OH, C₁₋C₆ alkoxy, or            phenyl groups,        -   (iii) each occurrence of R⁵ is independently H,            (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; and    -   (f) each occurrence of p is independently 2 or 3 where the        broken line represents an optional presence of one or more        additional carbon-carbon bonds that when present complete one or        more carbon-carbon double bonds.

Preferred compounds of formula III are those wherein each occurrence ofY is independently OH, COOR³, or COOH.

Other preferred compounds of formula III are those wherein p is 2.

Other preferred compounds of formula III are those wherein p is 3.

In yet another embodiment, the invention encompasses compounds offormula IIIa:

or a pharmaceutically acceptable salt, hydrate, solvate, thereof,wherein W¹, W² and Z_(m) are the same as compound III. Preferably incompound IIIa, W¹ and W² are independent C(R¹)(R²)—Y groups and eachoccurrence of Y is independently OH, COOR³, or COOH. Illustrativecompounds are illustrated below in Table 1. TABLE 1 Compounds of theInvention

I-15-Hydroxy-1-[4-(5-hydroxy-5-methyl-2-oxo-hexyl)-phenyl]-5-methyl-hexan-2-one

I-26-Hydroxy-1-[4-(6-hydroxy-5,5-dimethyl-2-oxo-hexyl)-phenyl]-5,5-dimethyl-hexan-2-one

I-36-[4-(5-Carboxy-5-methyl-2-oxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanoicacid

I-46-[4-(5,5-Dimethyl-2,6-dioxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanal

I-56-[4-(5-Methoxycarbonyl-5-methyl-2-opxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanoicacid methyl ester

I-62,2-Dimethyl-6-[4-(5-methyl-oxo-5-phenoxycarbonyl-hexyl)-phenyl]-5-oxo-hexanoicacid phenyl ester

I-76-[4-(5-Benzyloxycarbonyl-5-methyl-2-oxo-hexyl)-phenyl]-2,2-dimethyl-5-oxo-hexanoicacid benzyl ester

I-82-Methyl-6-[4-(5-methyl-2-oxo-5-sulfo-hexyl)-phenyl]-5-oxo-hexane-2-sulfonicacid

I-9 Phosphoric acidmono-{1,1-dimethyl-5-[4-(5-methyl-2-oxo-5-phosphonooxy-hexyl)-phenyl]-4-oxo-pentyl} ester

I-104-Hydroxy-1-[4-(4-hydroxy-4-methyl-pentanoyl)-phenyl]-4-methyl-pentan-1-one

I-115-Hydroxy-1-[4-(5-hydroxy-4,4-dimethyl-pentanoyl)-phenyl]-4,4-dimethyl-pentan-1-one

I-125-[4-(4-Carboxy-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanoicacid

I-135-[4-(4,4-Dimethyl-5-oxo-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanal

I-145-[4-(4-Methoxycarbonyl-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanoicacid methyl ester

I-152,2-Dimethyl-6-[4-(5-methyl-2-oxo-5-phenoxycarbonyl-hexyl)-phenyl]-5-oxo-hexanoicacid phenyl ester

I-165-[4-(4-Benzyloxycarbonyl-4-methyl-pentanoyl)-phenyl]-2,2-dimethyl-5-oxo-pentanoicacid benzyl ester

I-172-Methyl-5-[4-(4-methyl-4-sulfo-pentanoyl)-phenyl]-5-oxo-pentane-2-sulfonicacid

I-18 Phosphoric acidmono-{1,1-dimethyl-4-[4-(4-methyl-4-phosphonoxy-pentanoyl)-phenyl]-4-oxo-butyl} ester

Ib-1 2,12-Dihydroxy-2,12-dimethyl-tridecane-5,9-dione

Ib-2 1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-3 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid

Ib-4 2,2,12,12-Tetramethyl-5,9-dioxo-tridecandial

Ib-5 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dimethyl ester

Ib-6 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid diphenyl ester

Ib-7 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dibenzyl ester

Ib-8 2,12-Dimethyl-5,9-dioxo-tridecane-2,12-disulfonic acid

Ib-9 Phosphoric acidmono(1,1,11-trimethyl-4,8-dioxo-11-phosphonooxy-dodecyl) ester

Ib-102,12-Bis(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-112,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-12 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dicyanimide

Ib-13 Phosphoramidic acidmono[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-dioxo-dodecyl] ester

Ib-142,12-Dimethyl-2,12-bis-(amino-hydroxy-phosphoryloxy)-tridecane-5,9-dione

Ib-15 2,12-Dimethyl-2,12-bis-tetrazol-1-yl-tridecane-5,9-dione

Ib-16 2,12-Dimethyl-2,12-bis(1H-tetrazol-5-yl)-tridecane-5,9-dione

Ib-172,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-182,12-Bis(3-hydroxy-isoxazol-4-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-192,12-Bis(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-202,12-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-211-Ethyl-3-[11-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-1,1,11-trimethyl-4,8-dioxo-dodecyl]-imidazolidine-2,4-dione

Ib-222,12-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-232,12-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-242,12-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,12-dimethyl-tridecane-5,9-dione

Ib-25 1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecane-6,10-dione

Ib-26 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid

Ib-27 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedial

Ib-28 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanesioic acid dimethylester

Ib-29 2,2,12,12-Tetramethyl-5,9-dioxo-tetradecanedioic acid diphenylester

Ib-30 3,3,13,13-Tetramethyl-6,10,14-trioxo-16-phenyl-hexadecanoic acidbenzyl ester

Ib-31 2,2,12,12-Tetramethyl-5,9-dioxo-tridecane-1,13-disulfonic acid

Ib-32 Phosphoric acidmono-(2,2,12,12-tetramethyl-5,9-dioxo-13-phosphonooxy-tridecyl) ester

Ib-331,13-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-341,13-Bis(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-35 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide

Ib-36 Phosphoramidic acidmono-[13-(amino-hydroxy-phosphoryloxy)-2,2,12,12-tetramethyl-6,9-dioxo-tridecyl] ester

Ib-37 Phosphoramidic acidmono-[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-dioxo-dodecyl]ester

Ib-38 2,2,12,12-Tetramethyl-1,13-bis-tetrazol-1-yl-tridecane-5,9-dione

Ib-391,13-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-401,13-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-411,13-Bis-(3-hydroxy-isoxazol-4-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-421-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-13-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-431,13-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-441,13-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-451-Ethyl-3-[13-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-5,9-dioxo-tridecyl]-imidazolidine-2,4-dione

Ib-461,13-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-471,13-Bis-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-481,13-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-491,13-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,12,12-tetramethyl-tridecane-5,9-dione

Ib-50 2,11-Dihydroxy-2,11-dimethyl-dodecane-5,8-dione

Ib-51 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-52 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid

Ib-53 2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid

Ib-54 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial

Ib-55 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dimethyl ester

Ib-56 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester

Ib-57 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dibenzyl ester

Ib-58 Phosphoric acidmono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester

Ib-59 2,14-Dihydroxy-2,14-dimethyl-pentadecane-6,10-dione

Ib-60 1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-61 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid

Ib-62 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedial

Ib-63 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dimethylester

Ib-64 2,2,14,14-Tetramethyl-6,10-dioxo-hexadecanedioic acid diphenylester

Ib-65 2,2,14,14-Tetramethyl-6,10-dioxo-hexandecanedioic acid dibenzylester

Ib-66 2,14-Dimethyl-6,10-dioxo-pentadecane-2,1-4disulfonic acid

Ib-67 Phosphoric acidmono-(1,1,13-trimethyl-5,9-dioxo-13-phosphonooxy-tetradecyl) ester

Ib-682,14-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-692,14-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-70 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide

Ib-71 Phosphoroamidic acidmono[13-(amino-hydroxy-phosphoryloxy)-1,1,13-trimethyl-5,9-dioxo-tetradecyl] ester

Ib-722,14-Dimethyl-2,14-bis(amino-hydroxy-phosphoryloxy)-pentadecane-6,10-dione

Ib-73 2,14-Dimethyl-2,14-bis-tetrazol-1-yl-pentadecane-6,10-dione

Ib-74 2,14-Dimethyl-2,14-bis-(1H-tetrazol-5-yl)pentadecane-6,10-dione

Ib-752,14-Bis-(3-hydroxy-isoxazol-5-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-762,14-Bis-(3-hydroxy-isoxazol-4-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-772,14-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-782-(5-Hydroxy-4-oxo-4H-pyran-2-yl)-2,14-dimethyl-14-(5-methyl-4-oxo-4H-pyran-2-yl)-pentadecane-6,10-dione

Ib-792,14-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-802,14-Bis-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-812,14-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecane-6,10-dione

2,14-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,14-dimethyl-pentadecane-6,10-dione

Ib-83 1,14-Dihydroxy-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-84 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid

Ib-85 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedial

Ib-86 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecaendioic acid dimethylester

Ib-87 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanioic acid diphenyl ester

Ib-88 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid dibenzylester

Ib-89 2,2,11,11-Tetramethyl-5,8-dioxo-dodecane-1,12-disulfonic acid

Ib-90 Phosphoric acidmono-(2,2,11,11-tetramethyl-5,8-dioxo-12-phosphonooxy-dodecyl) ester

Ib-911,12-Bis-(4,6-dithiooxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-921,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dithione

Ib-93 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecaedioic acid dicyanimide

Ib-94 Phosphoramidic acidmono-[12-(amino-hydroxy-phosphoryloxy)-2,2,11,11-tetramethyl-5,8-dioxo-dodecyl] ester

Ib-952,2,11,11-Tetramethyl-1,12-bis-(aminohydroxyphosphoryloxy)-dodecane-5,8-dione

Ib-962,2,11,11-Tetramethyl-1,12-bis-(1H-tetrazol-5-yl)-dodecane-5,8-dione

Ib-971,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-981,12-Bis-(3-hydroxy-isoxaol-4-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-991-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-12-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-1001,12-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-1011,12-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-1021-Ethyl-3-[12-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl-5,8-dioxo-dodecyl]-imidazolidine-2,4-dione

Ib-1031-Ethyl-3-[12-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl-5,8-dioxo-dodecyl]-imidazolidine-2,4-dione

Ib-1041,12-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-1051,12-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-106 1,16-Dihydroxy-4,4,13,13-tetramethyl-hexadecane-7,10-dione

Ib-107 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid

Ib-108 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedial

Ib-109 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dimethylester

Ib-110 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid diphenylester

Ib-111 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dibenzylester

Ib-112 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecane-1,14-disulfonic acid

Ib-113 Phosphoric acidmono-(3,3,12,12-tetramethyl-6,9-dioxo-14-phosphonooxy-tetradecyl) ester

Ib-1141,14-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1151,14-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-116 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dicyanimide

Ib-117 Phosphoramidic acidmono-[14-(amino-hydroxy-phosphoryloxy)-3,3,12,12-tetramethyl-6,9-dioxo-tetradecyl] ester

Ib-1183,3,12,12-Tetramethyl-1,14-bis-(amino-hydroxy-phosphoryloxy)-tetradecane-6,9-dione

Ib-119 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione

Ib-120 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid

Ib-121 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial

Ib-122 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dimethyl ester

Ib-123 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester

Ib-124 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dibenzyl ester

Ib-125 2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid

Ib-126 Phosphoric acidmono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester

Ib-1272,11-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,11-dimethyl-dodecane-5,8-dione

Ib-1282,11-Bis-(4,6-dithio-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,11-dimethyl-dodecane-5,8-dione

Ib-129 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanimide

Ib-120 Phosphoramidic acidmono-[10-(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-dioxo-undecyl] ester

2,2,11,11-Tetramethyl-1,12-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dione

Ib-1323,3,12,12-Tetramethyl-1,14-bis-tetrazol-1-yl-tetradecane-6,9-dione

Ib-1333,3,12,12-Tetramethyl-1,14-bis-(1H-tetrazol-5-yl)-tetradecane-6,9-dione

Ib-1341,14-Bis-(3-hydroxy-isoxazol-5-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1351,14-Bis-(3-hydroxy-isoxazol-4-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1361-(5-Hydroxy-4-oxo-4H-pyran-2-yl)-14-(5-hydroxy-4-oxo-4H-pyran-3-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1371,14-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1381,14-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1391-Ethyl-3-[14-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-6,9-dioxo-tetradecyl]-imidazolidine-2,4-dione

Ib-1401-Ethyl-3-[14-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-6,9-dioxo-tetradecyl]-imidazolidine-2,4-dione

Ib-1411-Ethyl-3-[14-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-6,9-dioxo-tetradecyl]-imidazolidine-2,4-dithione

Ib-1421,14-Bis(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-1431,14-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-3,3,12,12-tetramethyl-tetradecane-6,9-dione

Ib-144 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione

Ib-145 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedial

Ib-146 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid dimethylester

Ib-147 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione

Ib-148 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid diphenylester

Ib-149 3,3,15,15-Tetramethyl-7,11-dioxo-heptanedioic acid dibenzyl ester

Ib-1502,11-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-2,11-dimethyl-dodecane-5,8-dione

Ib-1512,11-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,11-dimethyl-dodecane-5,8-dione

Ib-152 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanamide

Ib-153 Phosphoramidic acidmono-[10--(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-dioxo-undecyl] ester

Ib-1542,11-Dimethyl-2,11-bis-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dione

Ib-155 2,11-Dimethyl-2,11-bis-tetrazol-1-yl-dodecane-5,8-dione

Ib-156 2,11-Dimethyl-2,11-bis-(1H-tetrazol-5-yl)-dodecane-5,8-dione

Ib-157 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecane-1,15-disulfonic acid

Ib-158 Phosphoric acidmono-(2,2,14,14-0tetramethyl-6,10-dioxo-15-phosphonooxy-pentadecyl)ester

Ib-1591,15-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1601,15-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-161 3,3,15,15-Tetramethyl-7,11-dioxo-heptanedioic acid dicyanamide

Ib-162 Phosphoramidic acidmono-[16-(amino-hydroxy-phosphoryloxy)-4,4,15,15-tetramethyl-7,11-dioxo-hexadecyl] ester

Ib-1632,2,14,14-Tetramethyl-1,15-bis-(amino-hydroxy-phosphoryloxy)-pentadecane-6,10-dione

Ib-1642,2,14,14-Tetramethyl-1,15-bis-tetrazol-1-yl-pentadecane-6,10-dione

Ib-1652,2,14,14-Tetramethyl-1,15-bis-(1H-tetrazol-5-yl)-pentadecane-6,10-dione

Ib-1661,15-Bis-(3-hydroxy-isoxazol-5-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1671,15-Bis-(3-hydroxy-isoxazol-4-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1681-(5-Hydroxy-4-oxo-4H-pyran-3-yl)-15-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1691,15-Bis-(5-hydroxy-4-oxo-4H-pyran-2-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1701,15-Bis-(5-hydroxy-4-oxo-4H-pyran-3-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1711,15-Bis-(3-ethyl-2,5-dithio-imidazolidin-1-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1721-Ethyl-3-[15-(3-ethyl-2,5-dithioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl-6,10-dioxo-pentadecyl]-imidazolidine-2,4-dione

Ib-1731,15-Bis-(3-ethyl-2,5-dioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1741,15-Bis-(3-ethyl-5-oxo-2-thioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ib-1751,15-Bis-(3-ethyl-2-oxo-5-thioxo-imidazolidin-1-yl)-2,2,14,14-tetramethyl-pentadecane-6,10-dione

Ic-1 1,9-Bis-(tetrahydro-pyran-2-yloxy)-nonane-3,7-dione

Ic-2 1,9-Bis-(4-oxo-oxetan-2-yl)-nonane-3,7-dione

Ic-3 1,9-Bis-(2-oxo-oxetan-3-yl)-nonane-3,7-dione

Ic-4 1,9-Bis-(5-oxo-tetrahydrofuran-2-yl)-nonane-3,7-dione

Ic-5 1,9-Bis-(5-oxo-tetrahydrofuran-3-yl)-nonane-3,7-dione

Ic-6 1,9-Bis-(2-oxo-tetrahydrofuran-3-yl)-nonane-3,7-dione

{2-[9-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-3,7-dioxo-nonyl]-4-hydroxy-6-oxo-tetrahydropyran-4-yl)-acetic acid

Ic-8 1,9-Bis-(6-oxo-tetrahydropyran-2-yl)-nonane-3,7-dione

Ic-9 1,9-Bis-(6-oxo-tetrahydropyran-3-yl)-nonane-3,7-dione

Ic-10 1,9-Bis-(2-oxo-tetrahydropyran-4-yl)-nonane-3,7-dione

Ic-11 1,9-Bis-(2-oxo-tetrahydropyran-3-yl)-nonane-3,7-dione

Ic-12 1,11-Bis-(tetrahydro-pyran-2-yloxy)-undecane-4,8-dione

Ic-13 1,11-Bis-(2-oxo-oxetan-3-yl)-undecane-4,8-dione

Ic-14 1,11-Bis-(2-oxo-oxetan-3-yl)-undecane-4,8-dione

Ic-15 1,11-Bis-(5-oxo-tetrahydrofuran-2-yl)-undecane-4,8-dione

Ic-16 1,11-Bis-(5-oxo-tetrahydrofuran-3-yl)-undecane-4,8-dione

Ic-17 1,11-Bis-(2-oxo-tetrahydrofuran-3-yl)-undecane-4,8-dione

Ic-18{2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-4,8-dioxo-undecyl]-4-hydroxy-6-oxo-tetrahydropyran-4-yl}-acetic acid

Ic-19 1,11-Bis-(6-oxo-tetrahydropyran-2-yl)-undecane-4,8-dione

Ic-20 1,11-Bis-(6-oxo-tetrahydropyran-3-yl)-undecane-4,8-dione

Ic-21 1,11-Bis-(2-oxo-tetrahydropyran-4-yl)-undecane-4,8-dione

Ic-22 1,11-Bis-(2-oxo-tetrahydropyran-3-yl)-undecane-4,8-dione

IC-23 1,8-Bis-(tetrahydropyran-2-yloxy)-octane-3,6-dione

IC-24 1,8-Bis-(4-oxo-oxetan-2-yl)-octane-3,6-dione

IC-25 1,8-Bis-(2-oxo-oxetan-3-yl)-octane-3,6-dione

IC-26 1,8-Bis-(5-oxo-tetrahydro-furan-2-yl)-octane-3,6-dione

IC-27 1,8-Bis-(5-oxo-tetrahydro-furan-3-yl)-octane-3,6-dione

IC-28 1,8-Bis-(2-oxo-tetrahydro-furan-3-yl)-octane-3,6-dione

IC-29{2-[8-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-3,6-dioxo-octyl]-4-hydroxy-6-oxo-tetrahydro-pyran-4-yl}-acetic acid

IC-30 1,8-Bis-(6-oxo-tetrahydropyran-2-yl)-octane-3,6-dione

IC-31 1,8-Bis-(6-oxo-tetrahydropyran-3-yl)-octane-3,6-dione

IC-32 1,8-Bis-(2-oxo-tetrahydropyran-4-yl)-octane-3,6-dione

IC-33 1,8-Bis-(2-oxo-tetrahydropyran-3-yl)-octane-3,6-dione

II-1 1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecan-7-ene

II-2 12-Hydroxy-2,2,12-trimethyl-7-oxo-tridecanoic acid; compound withformaldehyde

II-3 11-Hydroperoxy-2,2,10,10-tetramethyl-6-oxo-undecanoic acid

II-4 1,11-Dihydroxy-2,2,10,10-tetramethyl-undecan-6-one

II-5 11-Hydroxy-2,2,10,10-tetramethyl-6-oxo-undecanoic acid

II-6 2,2,10,10-Tetramethyl-6-oxo-undecanedioic acid

II-7 1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecan-8-one

II-8 15-Hydroxy-2,2,14,14-tetramethyl-8-oxo-pentadecanoic acid

II-9 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid

II-10 2,2,12,12-Tetramethyl-7-oxo-tridecanedial

II-11 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid dimethyl ester

II-12 2,2,12,12-Tetramethyl-1,13-diphenyl-tridecane-1,7,13-trione

II-13 3,3,13,13-Tetramethyl-1,15-diphenyl-pentadecane-2,8,14-trione

II-14 2,12-Dimethyl-7-oxo-tridecane-2,12-disulfonic acid

II-15 Phosphoric acidmono-(1,1,11-trimethyl-6-oxo-11-phosphonooxy-dodecyl) ester

II-16 2,2,14,14-Tetramethyl-8-oxo-pentadecanedial

II-17 2,2,14,14-Tetramethyl-8-oxo-pentadecanedioic acid dimethyl ester

II-18 2,2,14,14-Tetramethyl-1,15-diphenyl-pentadecane-1,8,15-trione

II-19 3,3,15,15-Tetramethyl-1,17-diphenyl-heptadecane-2,9,16-trione

II-20 2,14-Dimethyl-8-oxo-pentadecane-2,14-disulfonic acid

II-21 Phosphoric acidmono-(1,1,13-trimethyl-7-oxo-13-phosphonooxy-tetradecyl) ester

II-22 1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecan-8-one

II-23 15-Hydroxy-3,3,13,13-tetramethyl-8-oxo-pentadecanoic acid

II-24 3,3,13,13-Tetramethyl-8-oxo-pentadecanedioic acid

II-25 1,13-Dihydroxy-3,3,11,11-tetramethyl-tridecan-7-one

II-26 13-Hydroxy-3,3,11,11-tetramethyl-7-oxo-tridecanoic acid

II-27 3,3,11,11-Tetramethyl-7-oxo-tridecanedioic acid

II-28 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecan-9-one

II-29 17-Hydroxy-3,3,15,15-tetramethyl-9-oxo-heptadecanoic acid

II-30 3,3,15,15-Tetramethyl-9-oxo-heptadecanedioic acid

II-31 1,17-Dihydroxy-4,4,14,14-tetramethyl-heptadecan-9-one

II-32 17-Hydroxy-4,4,14,14-tetramethyl-9-oxo-heptadecanoic acid

II-33 4,4,14,14-Tetramethyl-heptadecan-9-oxo-1,17-dicarboxylic acid

II-34 1,15-Dihydroxy-4,4,14,14-tetramethyl-pentadecan-8-one

II-35 15-Hydroxy-4,4,12,12-tetramethyl-8-oxo-pentadecanoic acid

II-36 4,412,12-Tetramethyl-8-oxo-pentadecanedioic acid

II-37 1,19-Dihydroxy-4,4,16,16-tetramethyl-nondecan-10-one

II-38 19-Hydroxy-4,4,16,16-tetramethyl-10-oxo-nonadecanoic acid

II-39 4,4,16,16-Tetramethyl-10-oxo-nonadecanedioic acid

II-405-[9-(4-Mercapto-3-methyl-2,6-dioxo-3,6-dihydro-2H-pyridin-1-yl)-1,1,9-trimethyl-5-oxo-decyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dione

II-412,10-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,10-dimethyl-undecan-6-one

II-42 2,2,10,10-Tetramethyl-6-oxo-undecanedioic acid bis-cyanoamide

II-43 Phosphoramidic acid mono-[9-(amino-hydroxy-phosphoryloxy)-1,1,9-trimethyl-5-oxo-decyl] ester

II-44 Phosphoramidic acidmono-]9-(amino-hydroxy-phosphoryloxy)-1,1,9-trimethyl-5-oxo- decyl]ester

II-452,12-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-dimethyl-tridecan-7-one

II-462,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridi-5-yl)-2,12-dimethyl-tridecan-7-one

II-47 2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid bis-cyanoamide

II-48 Phosphoramidic acid mono-[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-6-oxo-dodecyl] ester

II-49 Phosphoramidic acidmono-[11(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-6-oxo- dodecyl]ester

II-50 2,12-Dimethyl-2,12-bis-tetrazol-1-yl-tridecan-7-one

II-51 2,12-Dimethyl-2,12-bis-(1H-tetrazol-5-yl)-tridecan-7-one

II-52 2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-dimethyl-tridecan-7-one

II-53 2,12-Bis-(3-hydroxy-isoxazol-4-yl)-2,12-dimethyl-tridecan-7-one

II-544-[11-(4-oxo-oxetan-2-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-oxetan-2-one

II-553-[11-(4-oxo-oxetan-2-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-oxetan-2-one

II-565-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydro-furan-2-one

II-573-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydro-furan-2-one

II-584-[11-(5-oxo-tetrahydro-furan-3-yl)-1,1,11-Trimethyl-6-oxo-dodecyl]-dihydro-furan-2-one

II-59 2,12-Dimethyl-2,12-bis-(tetrahydro-pyran-2-yloxy)-tridecan-7-one

II-60{2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-1,1,11-trimethyl-6-oxo-dodecyl]-4-hydroxy- 6-oxo-tetrahydro-pyran-4-yl}-aceticacid

IIa-1 1,15-Dihydroxy-2,14-dimethyl-2,14-diphenyl-pentadecan-8-one

IIa-2 15-Hydroxy-2,14-dimethyl-8-oxo-2,14-diphenyl-pentadecanoic acid

IIa-3 2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedioic acid

IIa-4 1,13-Dihydroxy-2,12-dimethyl-2,12-diphenyl-tridecan-7-one

IIa-5 13-Hydroxy-2,12-dimethyl-7-oxo-2,12-diphenyl-tridecanoic acid

IIa-6 2,12-Dimethyl-7-oxo-2,12-diphenyl-tridecanedioic acid

IIa-7 1,11-Dihydroxy-2,10-dimethyl-2,10-diphenyl-undecn-6-one

IIa-8 11-Hydroxy-2,10-dimethyl-6-oxo-2,10-diphenyl-undecanoic acid

IIa-9 2,10-Dimethyl-6-oxo-2,10-diphenyl-undecandioic acid

IIa-10 2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedial

IIa-11 2,14-Dimethyl-8-oxo-2,14-diphenyl-pentadecanedioic acid dimethylester

IIa-12 2,14-Dimethyl-1,2,14,15-tetraphenyl-pentadecane-1,8,15-trione

IIa-13 3,15-Dimethyl-1,3,15,17-tetraphenyl-heptadecane-2,9,16-trione

IIa-14 8-Oxo-2,14-diphenyl-pentadecane-2,14-disulfonic acid

IIa-15 Phosphoric acidmono-(1-methyl-7-oxo-1,13-diphenyl-13-phosphonooxy-tetradecyl) ester

IIa-16 1,17-Dihydroxy-3,15-dimethyl-3,15-diphenyl-heptadecan-9-one

IIa-17 17-Hydroxy-3,15-dimethyl-9-oxo-3,15-diphenyl-heptadecanoic acid

IIa-18 3,15-Dimethyl-9-oxo-3,15-diphenyl-heotadecanedioic acid

IIa-19 1,15-Dihydroxy-3,13-dimethyl-3,13-diphenyl-pentadecan-8-one

IIa-20 15-Hydroxy-3,13-dimethyl-8-oxo-3,13-diphenyl-pentadecanoic acid

IIa-21 3,13-Dimethyl-8-oxo-3,13-diphenyl-pentadecanedioic acid

IIa-22 1,13-Dihydroxy-3,11-dimethyl-3,11-diphenyl-tridecan-7-one

IIa-23 13-Hydroxy-3,11-dimethyl-7-oxo-3,11-diphenyl-tridecanoic acid

IIa-24 3,11-Dimethyl-7-oxo-3,11-diphenyl-tridecanedioic acid

IIa-25 13-Hydroxy-3,11-dimethyl-7-oxo-3,11-diphenyl-tridecanoic acid

IIa-26 3,11-Dimethyl-7-oxo-3,11-diphenyl-tridecanedioic acid

IIa-27 1,19-Dihydroxy-4,16-dimethyl-4,16-diphenyl-nonadecan-10-one

IIa-28 19-Hydroxy-4,16-dimethyl-10-oxo-4,16-diphenyl-nonadecanoic acid

IIa-29 4,16-Dimethyl-10-oxo-4,16-diphenyl-nonadecanedioic acid

IIa-30 1,17-Dihydroxy-4,14-dimethyl-4,14-diphenyl-heptadecan-9-one

IIa-31 17-Hydroxy-4,14-dimethyl-9-oxo-4,14-diphenyl-heptadecanoic acid

IIa-32 4,14-Dimethyl-9-oxo-4,14-diphenyl-heptadecanedioic acid

IIa-33 1,15-Dihydroxy-4,12-dimethyl-4,12-diphenyl-pentadecan-8-one

IIa-34 15-Hydroxy-4,12-dimethyl-8-oxo-4,12-diphenyl-pentadecanoic acid

IIa-35 4,12-Dimethyl-8-oxo-4,12-diphenyl-pentadecanedioic acid

IIa-362,12-Bis-(4,6-dioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-diphenyl-tridecan-7-one

IIa-372,12-Bis-(4,6-dithioxo-2,3,3a,6-tetrahydro-4H-thieno[3,2-c]pyridin-5-yl)-2,12-diphenyl-tridecan-7-one

IIa-38 2,12-Dimethyl-2,12-diphenyl-7-oxo-tridecanedioic acidbis-cyanoamide

IIa-39 Phosphoramidic acid mono-[11-(amino-hydroxy-phosphoryloxy)-1-methyl-6-oxo-1,11-diphenyl-dodecyl] ester

IIa-40 Phosphoramidic acidmono-[11(amino-hydroxy-phosphoryloxy)-1,11-diphenyl-1-methyl-6-oxo-dodecyl] ester

IIa-41 2,12-Diphenyl-2,12-bis-tetrazol-1-yl-tridecan-7-one

IIa-42 2,12-Diphenyl-2,12-bis-(1H-tetrazol-5-yl)-tridecan-7-one

IIa-43 2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-diphenyl-tridecan-7-one

IIa-44 2,12-Bis-(3-hydroxy-isoxazol-4-yl)-2,12-diphenyl-tridecan-7-one

IIa-45 2,12-Diphenyl-2,12-bis-(tetrahydrop-pyran-2-yloxy)-tridecan-7-one

IIa-465-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]-dihydro-furan-2-one

IIa-474-[11-(4-oxo-oxetan-2-yl)-1,11-diphenyl-1-methyl-6-oxo-dodecyl]-oxetan-2-one

IIa-484-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]-dihydro-furan-2-one

IIa-493-[11-(5-oxo-tetrahydro-furan-2-yl)-1,11-Diphenyl-1-methyl-6-oxo-dodecyl]-dihydro-furan-2-one

IIa-50 {2-[11-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-1-methyl-6-oxo-1,11-diphenyl-dodecyl]-4-hydroxy-6-oxo-tetrahydro-pyran-4-yl}-acetic acid

III-15-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl)-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-25-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-35-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-45-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-55-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoicacid

III-65-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-76-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-86-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-96-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-propyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-106-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-116-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoicacid

III-126-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-propyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-136-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol

II-146-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]vinyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

III-156-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-cinyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

III-166-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-176-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-cinyl}-1,4-dioxo-cyclohexadien-2-yl}-2,2-dimethyl-hexanoic acid

III-186-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-1,4-dioxo-cyclohexadien-2-yl}-2,2-dimethyl-hexanoic acid

III-196-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-206-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-216-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-225-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-oxo-cyclohexan-2-yl)-2,2dimethyl-pentan-1-ol

III-235-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

III-245-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-vinyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

III-255-(6-{2-[6-(5-Hydroxy-4,4-dimthyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-265-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-275-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-vinyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-285-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-295-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2dimethyl-pentanoic acid

III-305-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-vinyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-316-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-326-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-336-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-346-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-356-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-366-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2yl)-2,2-dimethyl-hexanoic acid

III-375-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-385-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-395-(6-{2-[6-(4-Carboxy-4-4methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-ethyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-405-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-415-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoicacid

III-425-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-ethyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-436-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol

III-446-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

III-456-(6-{2-[6-(6-Carboxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

III-466-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-2-ol

6-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol III-476-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl}-1,4-dio

xo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid II-486-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl}-1,4-dioxo-c

yclohexadien-2-yl)-2,2-dimethyl-hexanoic acid III-496-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-506-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl

III-516-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-hexanoic acid

III-525-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol

III-535-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

III-545-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-phenyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

III-555-(6-{2-[6-(5-Hydroxy-4-methyl-pentyl)-1,4-dioxo-cyclohex-2-yl]-phenyl}-1,4-dioxo-cyclohex-2-yl)-2,2-dimethyl-pentan-1-ol

5-(6-{2-[6-(5-Hydroxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-575-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1,4-dioxo-cyclohexadien-2-yl]-phenyl}-1,4-dioxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-585-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-595-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoicacid

III-605-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-4,4-dimethyl-1-oxo-cyclohexadien-2-yl]-phenyl}-4,4-dimethyl-1-oxo-cyclohexadien-2-yl)-2,2-dimethyl-pentanoic acid

III-615-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol

III-625-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

III-635-(5-{3-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

III-646-(5-{3-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentandien-2-yl)-2,2-dimethyl-hexan-1-ol

III-656-(5-{3-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

6-(5-{3-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-propyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

III-676-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexan-1-ol

III-686-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid

III-696-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid

III-706-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-716-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

III-726-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

III-735-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol

III-745-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid

III-755-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid

III-765-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-775-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentandien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

III-785-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexan-1-ol

6-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentan-2-yl]vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid

III-816-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentan-2-yl]-vinyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-hexanoic acid

III-826-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexan-1-ol

III-836-(5-{2-[5-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

III-846-(5-{2-[5-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclopentadien-2-yl]-vinyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-hexanoic acid

III-855-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentan-1-ol

III-865-(5-{2-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

III-875-(5-{2-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentadien-2-yl]-ethyl}-1-oxo-cyclopentadien-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-15-(6-{3-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol

IIIa-25-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-35-(6-{3-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-46-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol

IIIa-56-(6-{3-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

IIIa-66-(6-{3-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-propyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

IIIa-76-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexan-1-ol

IIIa-86-(6-{2-[6-(6-Hydroxy-5,5-dimethyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

IIIa-96-(6-{2-[6-(5-Carboxy-5-methyl-hexyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-hexanoic acid

IIIa-105-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentan-1-ol

IIIa-115-(6-{2-[6-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-125-(6-{2-[6-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclohexan-2-yl]-ethyl}-1-oxo-cyclohexan-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-135-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]-propyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentan-1-ol

IIIa-145-(5-{3-[5-(5-Hydroxy-4,4-dimethyl-pentyl)-1-oxo-cyclopentan-2-yl]propyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid

IIIa-155-(5-{3-[5-(4-Carboxy-4-methyl-pentyl)-1-oxo-cyclopentan-2-yl]propyl}-1-oxo-cyclopentan-2-yl)-2,2-dimethyl-pentanoic acid

The compounds of the invention are useful in medical applications fortreating or preventing cardiovascular diseases, dyslipidemias,dyslipoproteinemias, disorders of glucose metabolism, Alzheimer'sDisease, Syndrome X, PPAR-associated disorders, septicemia, thromboticdisorders, obesity, pancreatitis, hypertension, renal diseases, cancer,inflammation, and impotence. As used herein, the phrase “compounds ofthe invention” means, collectively, the compounds of formulas I, II, andIII and pharmaceutically acceptable salts, hydrates, solvates,clathrates, enantiomers, diasteriomers, racemates, or mixtures ofsteroisomers thereof. Compounds of formula I encompass subgroup formulasIa, Ib, and Ic. Compounds of formula II encompass subgroup formula IIaand compounds of formula III encompass subgroup of formula IIIa. Thus,“compound of the invention” collectively means compound of formulas I,Ia, Ib, Ic, II, IIa, III, and IIIa and pharmaceutically acceptablesalts, hydrates, solvates, clathrates, enantiomers, diasteriomers,racemates, or mixtures of steroisomers thereof. The compounds of theinvention are identified herein by their chemical structure and/orchemical name. Where a compound is referred to by both a chemicalstructure and a chemical name, and the chemical structure and chemicalname conflict, the chemical structure is determinative of the compound'sidentity.

The present invention further provides pharmaceutical compositionscomprising one or more compounds of the invention and a pharmaceuticallyacceptable vehicle, excipient, or diluent. A pharmaceutically acceptablevehicle can comprise a carrier, excipient, diluent, or a mixturethereof. These pharmaceutical compositions are useful for treating orpreventing a disease or disorder including, but not limited to, aging,Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation,insulin resistance, lipid elimination in bile, modulating C reactiveprotein, obesity, oxysterol elimination in bile, pancreatitis,Parkinson's disease, a peroxisome proliferator activatedreceptor-associated disorder, phospholipid elimination in bile, renaldisease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), athrombotic disorder, or enhancing bile production, or enhancing reverselipid transport, inflammatory processes and diseases likegastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,systemic lupus erythematosus), scleroderma, ankylosing spondylitis, goutand pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism. Thesepharmaceutical composition are also useful for reducing the fat contentof meat in livestock and reducing the cholesterol content of eggs.

The present invention provides a method for treating or preventing aaging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation,insulin resistance, lipid elimination in bile, modulating C reactiveprotein, obesity, oxysterol elimination in bile, pancreatitis,Parkinson's disease, a peroxisome proliferator activatedreceptor-associated disorder, phospholipid elimination in bile, renaldisease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), athrombotic disorder, or enhancing bile production, or enhancing reverselipid transport, inflammatory processes and diseases likegastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,systemic lupus erythematosus), scleroderma, ankylosing spondylitis, goutand pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism,comprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a compound of theinvention and a pharmaceutically acceptable vehicle, excipient, ordiluent.

The present invention further encompasses a method for reducing the fatcontent of meat in livestock comprising administering to livestock inneed of such fat-content reduction a therapeutically effective amount ofa compound of the invention or a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable vehicle,excipient, or diluent.

The invention also encompasses a method for inhibited hepatic fatty acidand sterol synthesis comprising administering to a patient in needthereof a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a compound of theinvention and a pharmaceutically acceptable vehicle, excipient, ordiluent.

The invention also encompasses a method of treating or preventing adisease or disorder that is capable of being treated or prevented byincreasing HDL levels, which comprises administering to a patient inneed of such treatment or prevention a therapeutically effective amountof a compound of the invention and a pharmaceutically acceptablevehicle, excipient, or diluent.

The invention also encompasses a method of treating or preventing adisease or disorder that is capable of being treated or prevented bylowering LDL levels, which comprises administering to such patient inneed of such treatment or prevention a therapeutically effective amountof a compound of the invention and a pharmaceutically acceptablevehicle, excipient, or diluent.

The compounds of the invention favorably alter lipid metabolism inanimal models of dyslipidemia at least in part by enhancing oxidation offatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis andtherefore the invention also encompasses methods of treatment orprevention of metabolic syndrome disorders.

The present invention provides a method for reducing the cholesterolcontent of a fowl egg comprising administering to a fowl species atherapeutically effective amount of a compound of the invention or apharmaceutical composition comprising a compound of the invention and apharmaceutically acceptable vehicle, excipient, or diluent.

Thus, the compounds of the present invention are useful for thetreatment of vascular disease, such as cardiovascular disease, stroke,and peripheral vascular disease; dyslipidemia; dyslipoproteinemia; adisorder of glucose metabolism; Alzheimer's Disease; Syndrome X; aperoxisome proliferator activated receptor-associated disorder;septicemia; a thrombotic disorder; obesity; pancreatitis; hypertension;renal disease; cancer; inflammation; inflammatory muscle diseases, suchas polymylagia rheumatica, polymyositis, and fibrositis; impotence;gastrointestinal disease; irritable bowel syndrome; inflammatory boweldisease; inflammatory disorders, such as asthma, vasculitis, ulcerativecolitis, Crohn's disease, Kawasaki disease, Wegener's granulomatosis,(RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), andautoimmune chronic hepatitis; arthritis, such as rheumatoid arthritis,juvenile rheumatoid arthritis, and osteoarthritis; osteoporosis, softtissue rheumatism, such as tendonitis; bursitis; autoimmune disease,such as systemic lupus and erythematosus; scleroderma; ankylosingspondylitis; gout; pseudogout; non-insulin dependent diabetes mellitus;polycystic ovarian disease; hyperlipidemias, such as familialhypercholesterolemia (FH), familial combined hyperlipidemia (FCH);lipoprotein lipase deficiencies, such as hypertriglyceridemia,hypoalphalipoproteinemia, and hypercholesterolemia; lipoproteinabnormalities associated with diabetes; lipoprotein abnormalitiesassociated with obesity; and lipoprotein abnormalities associated withAlzheimer's Disease. The compounds and compositions of the invention areuseful for treatment or prevention of high levels of bloodtriglycerides, high levels of low density lipopotein cholesterol, highlevels of apolipoprotein B, high levels of lipoprotein Lp(a)cholesterol, high levels of very low density lipoprotein cholesterol,high levels of fibrinogen, high levels of insulin, high levels ofglucose, and low levels of high density lipoprotein cholesterol. Thecompounds and compositions of the invention also have utility fortreatment of NIDDM without increasing weight gain. The sulfoxide andbis-sulfoxide compounds and compositions of the invention may also beused to reduce the fat content of meat in livestock and reduce thecholesterol content of eggs.

The present invention may be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments of the invention.

3.1. BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the invention can be understood with reference to thefigures described below:

FIGS. 1 a to 1 v illustrates various preferred compounds of theinvention;

FIG. 2 illustrates the effect of one week of daily oral gavage treatmenton lipoprotein total cholesterol in chow-fed male Sprague-Dawly rats.

FIG. 3 illustrates the effect of one week of daily oral gavage treatmenton serum lipids in chow-fed male Sprague-Dawly rats;

FIG. 4 illustrates the effect of two weeks of daily oral gavagetreatment on lipoprotein total cholesterol in chow-fed obese femaleZucker rats;

FIG. 5 is a table illustrating the effect of two weeks of daily oralgavage treatment using a specific compound of the invention in chow-fedobese female Zucker rats; and

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds useful for treating orpreventing a aging, Alzheimer's Disease, cancer, cardiovascular disease,diabetic nephropathy, diabetic retinopathy, a disorder of glucosemetabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence,inflammation, insulin resistance, lipid elimination in bile, modulatingC reactive protein, obesity, oxysterol elimination in bile,pancreatitis, Parkinson's disease, a peroxisome proliferator activatedreceptor-associated disorder, phospholipid elimination in bile, renaldisease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), athrombotic disorder, or enhancing bile production, or enhancing reverselipid transport, inflammatory processes and diseases likegastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,systemic lupus erythematosus), scleroderma, ankylosing spondylitis, goutand pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism.

In this regard, the compounds of the invention are particularly usefulwhen incorporated in a pharmaceutical composition having a carrier,excipient, diluent, or a mixture thereof. A composition of the inventionneed not contain additional ingredients, such as an excipient, otherthan a compound of the invention. Accordingly, in one embodiment, thecompositions of the invention can omit pharmaceutically acceptableexcipients and diluents and can be delivered in a gel cap or drugdelivery device. Accordingly, the present invention provides methods fortreating or preventing aging, Alzheimer's Disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, septicemia, metabolic syndromedisorders (e.g., Syndrome X), a thrombotic disorder, or enhancing bileproduction, or enhancing reverse lipid transport, inflammatory processesand diseases like gastrointestinal disease, irritable bowel syndrome(IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerativecolitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),autoimmune disease (e.g., systemic lupus erythematosus), scleroderma,ankylosing spondylitis, gout and pseudogout, muscle pain:polymyositis/polymyalgia rheumatica/fibrositis; infection and arthritis,juvenile rheumatoid arthritis, tendonitis, bursitis and other softtissue rheumatism, comprising administering to a patient in need thereofa therapeutically effective amount of a compound or composition of theinvention.

In certain embodiments of the invention, a compound of the invention isadministered in combination with another therapeutic agent. The othertherapeutic agent provides additive or synergistic value relative to theadministration of a compound of the invention alone. The therapeuticagent can be a lovastatin; a thiazolidinedione or fibrate; abile-acid-binding-resin; a niacin; an anti-obesity drug; a hormone; atyrophostine; a sulfonylurea-based drug; a biguanide; an a-glucosidaseinhibitor; an apolipoprotein A-I agonist; apolipoprotein E; acardiovascular drug; an HDL-raising drug; an HDL enhancer; or aregulator of the apolipoprotein A-I, apolipoprotein A-IV and/orapolipoprotein genes.

4.1. Definitions and Abbreviations

-   Apo(a): apolipoprotein(a)-   Apo A-I: apolipoprotein A-I-   Apo B: apolipoprotein B-   Apo E: apolipoprotein E-   FH: Familial hypercholesterolemia-   FCH: Familial combined hyperlipidemia-   GDM: Gestational diabetes mellitus-   HDL: High density lipoprotein-   IDL: Intermediate density lipoprotein-   IDDM: Insulin dependent diabetes mellitus-   LDH: Lactate dehdyrogenase-   LDL: Low density lipoprotein-   Lp(a): Lipoprotein (a)-   MODY: Maturity onset diabetes of the young-   NIDDM: Non-insulin dependent diabetes mellitus-   PPAR: Peroxisome proliferator activated receptor-   RXR: Retinoid X receptor-   VLDL: Very low density lipoprotein

The term “compound A” means the compound1,13-dihydroxy-2,2,12,12-tetramethyl-tridecan-7-one having thestructure:

1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecan-7-one

The compounds of the invention can contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to the invention, the chemical structuresdepicted herein, and therefore the compounds of the invention, encompassall of the corresponding compound's enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures.

A compound of the invention is considered optically active orenantiomerically pure (i.e., substantially the R-form or substantiallythe S-form) with respect to a chiral center when the compound is about90% ee (enantiomeric excess) or greater, preferably, equal to or greaterthan 95% ee with respect to a particular chiral center. A compound ofthe invention is considered to be in enantiomerically-enriched form whenthe compound has an enantiomeric excess of greater than about 1% ee,preferably greater than about 5% ee, more preferably, greater than about10% ee with respect to a particular chiral center. A compound of theinvention is considered diastereomerically pure with respect to multiplechiral centers when the compound is about 90% de (diastereomeric excess)or greater, preferably, equal to or greater than 95% de with respect toa particular chiral center. A compound of the invention is considered tobe in diastereomerically-enriched form when the compound has andiastereomeric excess of greater than about 1% de, preferably greaterthan about 5% de, more preferably, greater than about 10% de withrespect to a particular chiral center. As used herein, a racemic mixturemeans about 50% of one enantiomer and about 50% of is correspondingenantiomer relative to all chiral centers in the molecule. Thus, theinvention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of compounds of Formulas I through III.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a patient, e.g., to an animal for veterinary use orfor improvement of livestock, or to a human for clinical use, thecompounds of the invention are administered in isolated form or as theisolated form in a pharmaceutical composition. As used herein,“isolated” means that the compounds of the invention are separated fromother components of either (a) a natural source, such as a plant orcell, preferably bacterial culture, or (b) a synthetic organic chemicalreaction mixture. Preferably, via conventional techniques, the compoundsof the invention are purified. As used herein, “purified” means thatwhen isolated, the isolate contains at least 95%, preferably at least98%, of a single ether compound of the invention by weight of theisolate.

The phrase “pharmaceutically acceptable salt(s),” as used hereinincludes, but are not limited to, salts of acidic or basic groups thatmay be present in the compounds of the invention. Compounds that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate))salts. Compounds of theinvention that include an amino moiety also can form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds of the invention that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium, sodiumlithium, zinc, potassium, and iron salts.

As used herein, the term “solvate” means a compound of the invention ora salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

As used herein, the term “hydrate” means a compound of the invention ora salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound of the inventionor a salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule (e.g., a solvent or water)trapped within.

“Altering lipid metabolism” indicates an observable (measurable) changein at least one aspect of lipid metabolism, including but not limited tototal blood lipid content, blood HDL cholesterol, blood LDL cholesterol,blood VLDL cholesterol, blood triglyceride, blood Lp(a), blood apo A-I,blood apo E and blood non-esterified fatty acids.

“Altering glucose metabolism” indicates an observable (measurable)change in at least one aspect of glucose metabolism, including but notlimited to total blood glucose content, blood insulin, the blood insulinto blood glucose ratio, insulin sensitivity, and oxygen consumption.

As used herein, the term “alkyl group” means a saturated, monovalentunbranched or branched hydrocarbon chain. Examples of alkyl groupsinclude, but are not limited to, (C₁₋C₆)alkyl groups, such as methyl,ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longeralkyl groups, such as heptyl, and octyl. An alkyl group can beunsubstituted or substituted with one or two suitable substituents.

An “alkenyl group” means a monovalent unbranched or branched hydrocarbonchain having one or more double bonds therein. The double bond of analkenyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkenyl groups include, but are not limited to(C₂₋C₆)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl,butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

An “alkynyl group” means monovalent unbranched or branched hydrocarbonchain having one or more triple bonds therein. The triple bond of analkynyl group can be unconjugated or conjugated to another unsaturatedgroup. Suitable alkynyl groups include, but are not limited to,(C₂₋C₆)alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, 4-methyl-I-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. An alkynyl group can be unsubstituted or substitutedwith one or two suitable substituents.

An “aryl group” means a monocyclic or polycyclic-aromatic radicalcomprising carbon and hydrogen atoms. Examples of suitable aryl groupsinclude, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl,indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclicmoieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can beunsubstituted or substituted with one or two suitable substituents.Preferably, the aryl group is a monocyclic ring, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl”.

A “heteroaryl group” means a monocyclic- or polycyclic aromatic ringcomprising carbon atoms, hydrogen atoms, and one or more heteroatoms,preferably 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heteroaryl groups include,but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazyl,triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and(1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl,thiophenyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl, andoxazolyl. A heteroaryl group can be unsubstituted or substituted withone or two suitable substituents. Preferably, a heteroaryl group is amonocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to3 heteroatoms, referred to herein as “(C₂₋C₅)heteroaryl”.

A “cycloalkyl group” means a monocyclic or polycyclic saturated ringcomprising carbon and hydrogen atoms and having no carbon-carbonmultiple bonds. Examples of cycloalkyl groups include, but are notlimited to, (C₃₋C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted by one or two suitable substituents. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

A “heterocycloalkyl group” means a monocyclic or polycyclic ringcomprising carbon and hydrogen atoms and at least one heteroatom,preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, andsulfur, and having no unsaturation. Examples of heterocycloalkyl groupsinclude pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl,piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino,and pyranyl. A heterocycloalkyl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, theheterocycloalkyl group is a monocyclic or bicyclic ring, morepreferably, a monocyclic ring, wherein the ring comprises from 3 to 6carbon atoms and form 1 to 3 heteroatoms, referred to herein as (C₁₋₆)heterocycloalkyl.

As used herein a “heterocyclic radical” or “heterocyclic ring” means aheterocycloalkyl group or a heteroaryl group.

The term “alkoxy group” means an —O-alkyl group, wherein alkyl is asdefined above. An alkoxy group can be unsubstituted or substituted withone or two suitable substituents. Preferably, the alkyl chain of analkyloxy group is from 1 to 6 carbon atoms in length, referred to hereinas “(C₁₋C₆)alkoxy”.

The term “aryloxy group” means an —O-aryl group, wherein aryl is asdefined above. An aryloxy group can be unsubstituted or substituted withone or two suitable substituents. Preferably, the aryl ring of anaryloxy group is a monocyclic ring, wherein the ring comprises 6 carbonatoms, referred to herein as “(C₆)aryloxy”.

The term “benzyl” means —CH₂-phenyl.

The term “phenyl” means —C₆H₅. A phenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

A “hydrocarbyl” group means a monovalent group selected from(C₁₋C₈)alkyl, (C₂₋C₈)alkenyl, and (C₂₋C₈)alkynyl, optionally substitutedwith one or two suitable substituents. Preferably, the hydrocarbon chainof a hydrocarbyl group is from 1 to 6 carbon atoms in length, referredto herein as “(C₁₋C₆)hydrocarbyl”.

A “carbonyl” group is a divalent group of the formula —C(O)—.

An “alkoxycarbonyl” group means a monovalent group of the formula —C(O)—alkoxy. Preferably, the hydrocarbon chain of an alkoxycarbonyl group isfrom 1 to 8 carbon atoms in length, referred to herein as a “loweralkoxycarbonyl” group.

A “carbamoyl” group means the radical —C(O)N(R′)₂, wherein R′ is chosenfrom the group consisting of hydrogen, alkyl, and aryl.

As used herein, “halogen” means fluorine, chlorine, bromine, or iodine.Correspondingly, the meaning of the terms “halo” and “Hal” encompassfluoro, chloro, bromo, and iodo.

As used herein, a “suitable substituent” means a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: (C₁₋C₈)alkyl;(C₁₋C₈)alkenyl; (C₁₋C₈)alkynyl; (C₆)aryl; (C₂₋C₅)heteroaryl;(C₃-C₇)cycloalkyl; (C₁₋C₈)alkoxy; (C₆)aryloxy; —CN; —OH; oxo; halo,—CO₂H; —NH₂; —NH((C₁₋C₈)alkyl); —N((C₁₋C₈)alkyl)₂; —NH((C₆)aryl);—N((C₆)aryl)₂; —CHO; —CO((C₁₋C₈)alkyl); —CO((C₆)aryl);—CO₂((C₁₋C₈)alkyl); and —CO₂((C₆)aryl). One of skill in the art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compound of the invention.

4.2. Synthesis of the Compounds of the Invention

The compounds of the invention can be obtained via the syntheticmethodology illustrated in Schemes 1-8. Starting materials useful forpreparing the compounds of the invention and intermediates thereof, arecommercially available or can be prepared from commercially availablematerials using known synthetic methods and reagents.

Scheme 1 illustrates the synthesis of mono-protected diols of theformula X, wherein n is an integer ranging from 0 to 4 and R¹ and R² areas defined above, and E is a leaving group as defined below. Scheme 1first outlines the synthesis of mono-protected diols X, wherein n is 0,where esters 4 are successively reacted with a first ((R¹)_(p-)M) then asecond ((R²)_(p-)M) organometallic reagent providing ketones 5 andalcohols 6, respectively. M is a metal group and p is the metal'svalency value (e.g., the valency of Li is 1 and that of Zn is 2).Suitable metals include, but are not limited to, Zn, Na, Li, and—Mg-Hal, wherein Hal is a halide selected from iodo, bromo, or chloro.Preferably, M is —Mg-Hal, in which case the organometallic reagents,(R¹)_(p-)Mg-Hal and (R²)_(p-)Mg-Hal, are known in the art as a Grignardreagents. Esters 4 are available commercially (e.g., Aldrich ChemicalCo., Milwaukee, Wis.) or can be prepared by well-known syntheticmethods, for example, via esterification of the appropriate5-halovaleric acid (commercially available, e.g., Aldrich Chemical Co.,Milwaukee, Wis.). Both (R¹)_(p-)M and (R²)_(p-)M are availablecommercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or can beprepared by well-known methods (see e.g., Kharasch et al., GrignardReactions of Non-Metallic Substances; Prentice-Hall, Englewood Cliffs,N.J., pp. 138-528 (1954) and Hartley; Patai, The Chemistry of theMetal-Carbon Bond, Vol. 4, Wiley: New York, pp. 159-306 and pp. 162-175(1989), both citations are hereby expressly incorporated herein byreference). The reaction of a first ((R¹))_(p-)M) then a second((R²)_(p-)M) organometallic reagent with esters 4 can be performed usingthe general procedures referenced in March, J. Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.920-929 and Eicher, Patai, The Chemistry of the Carbonyl Group, pt. 1,pp. 621-693; Wiley: New York, (1966), hereby expressly incorporatedherein by reference. For example, the synthetic procedure described inComins et al., 1981, Tetrahedron Lett. 22:1085, hereby expresslyincorporated herein by reference, can be used. As one example, thereaction can be performed by adding an organic solution of (R¹)_(p-)M(about 0.5 to about 1 equivalents) to a stirred, cooled (about 0° C. toabout −80° C.) solution comprising esters 4, under an inert atmosphere(e.g., nitrogen) to give a reaction mixture comprising ketones 5.Preferably, (R¹)_(p-)M is added at a rate such that the reaction-mixturetemperature remains within about one to two degrees of the initialreaction-mixture temperature. The progress of the reaction can befollowed by using an appropriate analytical method, such as thin-layerchromatography or high-performance-liquid chromatography. Next, anorganic solution of (R²)_(p-)M (about 0.5 to about 1 equivalent) isadded to the reaction mixture comprising ketones 5 in the same mannerused to add (R¹)_(p-)M. After the reaction providing alcohols 6 issubstantially complete, the reaction mixture can be quenched and theproduct can be isolated by workup. Suitable solvents for obtainingalcohols 6 include, but are not limited to, dichloromethane, diethylether, tetrahydrofuran, benzene, toluene, xylene, hydrocarbon solvents(e.g., pentane, hexane, and heptane), and mixtures thereof. Preferably,the organic solvent is diethyl ether or tetrahydrofuran. Next, alcohols6 are converted to mono-protected diols X, wherein n is 0, using thewell-known Williamson ether synthesis. This involves reacting alcohols 6with —O—PG, wherein —PG is a hydroxy-protecting group. For a generaldiscussion of the Williamson ether synthesis, See March, J. AdvancedOrganic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992,pp. 386-387, and for a list of procedures and reagents useful in theWilliamson ether synthesis, See, for example, Larock ComprehensiveOrganic Transformations; VCH: New York, 1989, pp. 446-448, both of whichreferences are incorporated herein by reference. As used herein, a“hydroxy-protecting group” means a group that is reversibly attached toa hydroxy moiety that renders the hydroxy moiety unreactive during asubsequent reaction(s) and that can be selectively cleaved to regeneratethe hydroxy moiety once its protecting purpose has been served. Examplesof hydroxy-protecting groups are found in Greene, T. W., ProtectiveGroups in Organic Synthesis, 3rd edition 17-237 (1999), hereby expresslyincorporated herein by reference. Preferably, the hydroxy-protectinggroup is stable in a basic reaction medium, but can be cleaved by acid.Examples of suitable base-stable acid-labile hydroxy-protecting groupssuitable for use with the invention include, but are not limited to,ethers, such as methyl, methoxy methyl, methylthiomethyl,methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,o-nitrobenzyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, and triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly straight chain ethers, such as methyl ether,methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether,bis(2-chloroethoxy)methyl ether. Preferably —PG is methoxymethyl(CH₃OCH₂—). Reaction of alcohols 6 with —O—PG under the conditions ofthe Williamson ether synthesis involves adding a base to a stirredorganic solution comprising HO—PG (e.g., methoxymethanol), maintained ata constant temperature within the range of about 0° C. to about 80° C.,preferably at about room temperature. Preferably, the base is added at arate such that the reaction-mixture temperature remains within about oneto two degrees of the initial reaction-mixture temperature. The base canbe added as an organic solution or in undiluted form. Preferably, thebase will have a base strength sufficient to deprotonate a proton,wherein the proton has a pK_(a) of greater than about 15, preferablygreater than about 20. As is well known in the art, the pK_(a) is ameasure of the acidity of an acid H-A, according to the equationpK_(a)=−log K_(a), wherein K_(a) is the equilibrium constant for theproton transfer. The acidity of an acid H-A is proportional to thestability of its conjugate base -A. For tables listing pK_(a) values forvarious organic acids and a discussion on pK_(a) measurement, see March,J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, pp. 248-272, incorporated herein by reference. Suitable basesinclude, but are not limited to, alkylmetal bases such as methyllithium,n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium,phenyl sodium, and phenyl potassium; metal amide bases such as lithiumamide, sodium amide, potassium amide, lithium tetramethylpiperidide,lithium diisopropylamide, lithium diethylamide, lithiumdicyclohexylamide, sodium hexamethyldisilazide, and lithiumhexamethyldisilazide; and hydride bases such as sodium hydride andpotassium hydride. The preferred base is lithium diisopropylamide.Solvents suitable for reacting alcohols 6 with —OPG include, but are notlimited, to dimethyl sulfoxide, dichloromethane, ethers, and mixturesthereof, preferably tetrahydrofuran. After addition of the base, thereaction mixture can be adjusted to within a temperature range of about0° C. to about room temperature and alcohols 6 can be added, preferablyat a rate such that the reaction-mixture temperature remains withinabout one to two degrees of the initial reaction-mixture temperature.Alcohols 6 can be diluted in an organic solvent or added in theirundiluted form. The resulting reaction mixture is stirred until thereaction is substantially complete as determined by using an appropriateanalytical method, preferably by gas chromatography, then themono-protected diols X can be isolated by workup and purification.

Next, Scheme 1 outlines a method useful for synthesizing mono-protecteddiols X, wherein n is 1. First, compounds 7, wherein E is a suitableleaving group, are reacted with compounds 8, wherein R¹ and R² are asdefined above and R⁸ is H, (C₁₋C₆)alkyl or (C₆)aryl, providing compounds9. Suitable leaving groups are well known in the art, for example, butnot limited to halides, such as chloride, bromide, and iodide; aryl- oralkylsulfonyloxy, substituted arylsulfonyloxy (e.g., tosyloxy ormesyloxy); substituted alkylsulfonyloxy (e.g., haloalkylsulfonyloxy);(C₆)aryloxy or subsituted (C₆)aryloxy; and acyloxy groups. Compounds 7are available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.)or can be prepared by well-known methods such as halogenation orsulfonation of butanediol. Compounds 8 are also available commercially(e.g., Aldrich Chemical Co., Milwaukee, Wis.) or by well-known methods,such as those listed in Larock Comprehensive Organic Transformations;Wiley-VCH: New York, 1999, pp. 1754-1755 and 1765. A review onalkylation of esters of type 8 is given by J. Mulzer in ComprehensiveOrganic Functional Transformations, Pergamon, Oxford 1995, pp. 148-151and exemplary synthetic procedures for reacting compounds 7 withcompounds 8 are described in U.S. Pat. No. 5,648,387, column 6 andAckerly, et al., J. Med. Chem. 1995, pp. 1608, all of which citationsare hereby expressly incorporated herein by reference. The reactionrequires the presence of a suitable base. Preferably, a suitable basewill have a pK_(a) of greater than about 25, more preferably greaterthan about 30. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; hydridebases such as sodium hydride and potassium hydride. Metal amide bases,such as lithium diisopropylamide are preferred. Preferably, to reactcompounds 7 with compounds 8, a solution of about 1 to about 2equivalents of a suitable base is added to a stirred solution comprisingesters 8 and a suitable organic solvent, under an inert atmosphere, thesolution maintained at a constant temperature within the range of about−95° C. to about room temperature, preferably at about −78° C. to about−20° C. Preferably, the base is diluted in a suitable organic solventbefore addition. Preferably, the base is added at a rate of about 1.5moles per hour. Organic solvents suitable for the reaction of compounds7 with the compounds 8 include, but are not limited to, dichloromethane,diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide,benzene, toluene, xylene, hydrocarbon solvents (e.g., pentane, hexane,and heptane), and mixtures thereof. After addition of the base, thereaction mixture is allowed to stir for about 1 to about 2 hours, and acompound 7, preferably dissolved in a suitable organic solvent, isadded, preferably at a rate such that the reaction-mixture temperatureremains within about one to two degrees of the initial reaction-mixturetemperature. After addition of compounds 7, the reaction-mixturetemperature can be adjusted to within a temperature range of about −20°C. to about room temperature, preferably to about room temperature, andthe reaction mixture is allowed to stir until the reaction issubstantially complete as determined by using an appropriated analyticalmethod, preferably thin-layer chromatography or high-performance liquidchromatography. Then the reaction mixture is quenched and compounds 9,wherein n is 1 can be isolated by workup. Compounds 10 are thensynthesized by reacting compounds 9 with —O—PG according to the protocoldescribed above for reacting alcohols 6 with —O—PG. Next, compounds 10can be converted to mono-protected diols X, wherein n is 1, by reductionof the ester group of compounds 10 to an alcohol group with a suitablereducing agent. A wide variety of reagents are available for reductionof such esters to alcohols, e.g., see M. Hudlicky, Reductions in OrganicChemistry, 2nd ed., 1996 pp. 212-217, hereby expressly incorporatedherein by reference. Preferably, the reduction is effected with ahydride type reducing agent, for example, lithium aluminum hydride,lithium borohydride, lithium triethyl borohydride, diisobutylaluminumhydride, lithium trimethoxyaluminum hydride, or sodiumbis(2-methoxy)aluminum hydride. For exemplary procedures for reducingesters to alcohols, see Nystrom et al., 1947, J. Am. Chem. Soc. 69:1197;and Moffet et al., 1963, Org. Synth., Collect. 834(4), lithium aluminumhydride; Brown et al., 1965, J. Am. Chem. Soc. 87:5614, lithiumtrimethoxyaluminum hydride; Cerny et al., 1969, Collect. Czech. Chem.Commun. 34:1025, sodium bis(2-methoxy)aluminum hydride; Nystrom et al.,1949, J. Am. Chem. 71:245, lithium borohydride; and Brown et al., 1980,J. Org. Chem. 45:1, lithium triethyl borohydride, all of which citationsare hereby expressly incorporated herein by reference. Preferably, thereduction is conducted by adding an organic solution of compounds 10 toa stirred mixture comprising a reducing agent, preferably lithiumaluminum hydride, and an organic solvent. During the addition, thereaction mixture is maintained at a constant temperature within therange of about −20° C. to about 80° C., preferably at about roomtemperature. Organic solvents suitable for reacting 9 with —OPG include,but are not limited to, dichloromethane, diethyl ether, tetrahydrofuranor mixtures thereof, preferably tetrahydrofuran. After the addition, thereaction mixture is stirred at a constant temperature within the rangeof about room temperature to about 60° C., until the reaction issubstantially complete as determined by using an appropriate analyticalmethod, preferably thin-layer chromatography or high-performance-liquidchromatography. Then the reaction mixture can be quenched andmono-protected diols X, wherein n is 1, can be isolated by workup andpurification.

Scheme 1 next illustrates a three step synthetic sequence forhomologating mono-protected diols X comprising: (a) halogenation(converting —CH₂OH to —CH₂₋Hal); (b) carbonylation (replacing -Hal with—CHO); and (c) reduction (converting —CHO to —CH₂OH), wherein a reactionsequence of (a), (b), and (c) increases the value of n by 1. In step (a)protected halo-alcohols 11, wherein Hal is a halide selected from thegroup of chloro, bromo, or iodo, preferably iodo, can be prepared byhalogenating mono-protected diols X, by using well-known methods (for adiscussion of various methods for conversion of alcohols to halides seeMarch, J. Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, pp. 431-433, hereby expressly incorporatedherein by reference). For example, protected iodo-alcohols 11 can besynthesized starting from mono-protected diols X by treatment withPh₃/I₂/imidazole (Garegg et al., 1980, J.C.S Perkin I 2866);1,2-dipheneylene phosphorochloridite/I₂ (Corey et al., 1967, J. Org.Chem. 82:4160); or preferably with Me₃SiCl/NaI (Olah et al., 1979, J.Org. Chem. 44:8, 1247), all of which citations are hereby expresslyincorporated herein by reference. Step (b); carbonylation of alkylhalides, such as protected halo-alcohols 11, is reviewed in Olah et al.,1987, Chem Rev. 87:4, 671; and March, J., Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 483-484, both ofwhich are hereby expressly incorporated herein by reference). Protectedhalo-alcohols 11 can be carbonylated with Li(BF₃.Et₂O)/HCONMe₂ using theprocedure described in Maddaford et al., 1993, J. Org. Chem. 58:4132;Becker et al., 1982, J. Org. Chem. 3297; or Myers et al., 1992, J. Am.Chem. Soc. 114:9369 or, alternatively, with anorganometallic/N-formylmorpholine using the procedure described in Olahet al., 1984, J. Org. Chem. 49:3856 or Vogtle et al., 1987, J. Org.Chem. 52:5560, all of which citations are hereby expressly incorporatedherein by reference. The method described in Olah et al., 1984, J. Org.Chem. 49:3856 is preferred. Reduction step (c) useful for synthesizingmono-protected diols X from aldehydes 12, can be accomplished bywell-known methods in the art for reduction of aldehydes to thecorresponding alcohols (for a discussion see M. Hudlicky, Reductions inOrganic Chemistry, 2nd ed., 1996 pp 137-139), for example, by catalytichydrogenation (see e.g., Carothers, 1949, J. Am. Chem. Soc. 46:1675) or,preferably by reacting aldehydes 12 with a hydride reducing agent, suchas lithium aluminum hydride, lithium borohydride, sodium borohydride(see e.g., the procedures described in Chaikin et al., 1949, J. Am.Chem. Soc. 71:3245; Nystrom et al., 1947, J. Am. Chem. Soc. 69:1197; andNystrom et al., 1949, J. Am. Chem. 71:3245, all of which are herebyexpressly incorporated herein by reference). Reduction with lithiumaluminum hydride is preferred.

Scheme 2 outlines the method for the synthesis of protected alcohols 12awherein Y, R¹, R², Z, and m are defined as above. Protected alcohols 12acorrespond to compounds of the formula W⁽¹⁾⁽²⁾Zm-OPG, wherein W⁽¹⁾⁽²⁾⁻isC(R¹)(R²)—Y.

Protected alcohols 16, wherein Y comprises a —C(O)OH group, can besynthesized by oxidizing mono-protected diols X with an agent suitablefor oxidizing a primary alcohol to a carboxylic acid (for a discussionsee M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186,1990, pp. 127-130, hereby expressly incorporated herein by reference).Suitable oxidizing agents include, but are not limited to, pyridiniumdichromate (Corey et al., 1979, Tetrahedron Lett. 399); manganesedioxide (Ahrens et al., 1967, J. Heterocycl. Chem. 4:625); sodiumpermanganate monohydrate (Menger et al., 1981, Tetrahedron Lett.22:1655); and potassium permanganate (Sam et al., 1972, J. Am. Chem.Soc. 94:4024), all of which citations are hereby expressly incorporatedherein by reference. The preferred oxidizing reagent is pyridiniumdichromate. In an alternative synthetic procedure, protected alcohols16, wherein Y comprises a —C(O)OH group, can be synthesized by treatmentof protected halo-alcohols 15, wherein X is iodo, with CO or CO₂, asdescribed in Bailey et al., 1990, J. Org. Chem. 55:5404 and Yanagisawaet al., 1994, J. Am. Chem. Soc. 116:6130, the two of which citations arehereby expressly incorporated herein by reference. Protected alcohols16, wherein Y comprises —C(O)OR⁵, wherein R⁵ is as defined above, can besynthesized by oxidation of mono-protected diols X in the presence ofR⁵OH (see generally, March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, p. 1196). An exemplaryprocedure for such an oxidation is described in Stevens et al., 1982,Tetrahedron Lett. 23:4647 (HOCl); Sundararaman et al., 1978, TetrahedronLett. 1627 (O₃/KOH); Wilson et al., 1982, J. Org. Chem. 47:1360(t-BuOOH/Et₃N); and Williams et al., 1988, Tetrahedron Lett. 29:5087(Br₂), the four of which citations are hereby expressly incorporatedherein by reference. Preferably, protected alcohols 16, wherein Ycomprises a —C(O)OR⁵ group are synthesized from the correspondingcarboxylic acid (i.e., 16, wherein Y comprises —C(O)OH) byesterification with R⁵OH (e.g., see March, J., Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p.393-394, hereby expressly incorporated herein by reference). In anotheralternative synthesis, protected alcohols 16, wherein Y comprises—C(O)OR⁵, can be prepared from protected halo-alcohols 14 bycarbonylation with transition metal complexes (see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 484-486; Urata et al., 1991, Tetrahedron Lett. 32:36,4733); and Ogata et al., 1969, J. Org. Chem. 3985, the three of whichcitations are hereby expressly incorporated herein by reference).

Protected alcohols 16, wherein Y comprises —OC(O)R⁵, wherein R⁵ is asdefined above, can be prepared by acylation of mono-protected diols Xwith a carboxylate equivalent such as an acyl halide (i.e., R⁵C(O)-Hal,wherein Hal is iodo, bromo, or chloro, see e.g., March, J. AdvancedOrganic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992,p. 392 and Org. Synth. Coll. Vol. III, Wiley, NY, pp. 142, 144, 167, and187 (1955)) or an anhydride (i.e., R⁵C(O)—O—(O)CR⁵, see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 392-393 and Org. Synth. Coll. Vol. III, Wiley, NY, pp. 11,127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955), all of whichcitations are hereby expressly incorporated herein by reference).Preferably, the reaction is conducted by adding a base to a solutioncomprising mono-protected diols X, a carboxylate equivalent, and anorganic solvent, which solution is preferably maintained at a constanttemperature within the range of 0° C. to about room temperature.Solvents suitable for reacting mono-protected diols X with a carboxylateequivalent include, but are not limited to, dichloromethane, toluene,and ether, preferably dichloromethane. Suitable bases include, but arenot limited to, hydroxide sources, such as sodium hydroxide, potassiumhydroxide, sodium carbonate, or potassium carbonate; or an amine such astriethylamine, pyridine, or dimethylaminopyridine, amines are preferred.The progress of the reaction can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography and when substantially complete, theproduct can be isolated by workup and purified if desired.

Protected alcohols 16, wherein Y comprises one of the followingphosphate ester groups

wherein R⁶ is defined as above, can be prepared by phosphorylation ofmono-protected diols X according to well-known methods (for a generalreviews, see Corbridge Phosphorus: An Outline of its Chemistry,Biochemistry, and Uses, Studies in Inorganic Chemistry, 3rd ed., pp.357-395 (1985); Ramirez et al., 1978, Acc. Chem. Res. 11:239; andKalckare Biological Phosphorylations, Prentice-Hall, New York (1969); J.B. Sweeny in Comprehensive Organic Functional Group Transformations, A.R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon: Oxford, 1995,vol 2, pp. 104-109, the four of which are hereby expressly incorporatedherein by reference). Protected alcohols 16 wherein Y comprises amonophosphate group of the formula:

wherein R⁶ is defined as above, can be prepared by treatment ofmono-protected diol X with phosphorous oxychloride in a suitablesolvent, such as xylene or toluene, at a constant temperature within therange of about 100C to about 150° C. for about 2 hours to about 24hours. After the reaction is deemed substantially complete, by using anappropriate analytical method, the reaction mixture is hydrolyzed withR⁶—OH. Suitable procedures are referenced in Houben-Weyl, Methoden derOrganische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2, pp.143-210 and 872-879, hereby expressly incorporated herein by reference.Alternatively, when both R⁶ are hydrogen, can be synthesized by reactingmono-protected diols X with silyl polyphosphate (Okamoto et al., 1985,Bull Chem. Soc. Jpn. 58:3393, hereby expressly incorporated herein byreference) or by hydrogenolysis of their benzyl or phenyl esters (Chenet al., 1998, J. Org. Chem. 63:6511, hereby expressly incorporatedherein by reference). In another alternative procedure, when R⁶ is(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl, the monophosphateesters can be prepared by reacting mono-protected diols X withappropriately substituted phophoramidites followed by oxidation of theintermediate with m-chloroperbenzoic acid (Yu et al., 1988, TetrahedronLett. 29:979, hereby expressly incorporated herein by reference) or byreacting mono-protected diols X with dialkyl or diaryl substitutedphosphorochloridates (Pop, et al, 1997, Org. Prep. and Proc. Int.29:341, hereby expressly incorporated herein by reference). Thephosphoramidites are commercially available (e.g., Aldrich Chemical Co.,Milwaukee, Wis.) or readily prepared according to literature procedures(see e.g., Uhlmann et al. 1986, Tetrahedron Lett. 27:1023 and Tanaka etal., 1988, Tetrahedron Lett. 29:199, both of which are hereby expresslyincorporated herein by reference). The phosphorochloridates are alsocommercially available (e.g., Aldrich Chemical Co., Milwaukee, Wis.) orprepared according to literature methods (e.g., Gajda et al, 1995,Synthesis 25:4099. In still another alternative synthesis, protectedalcohols 16, wherein Y comprises a monophosphate group and R⁶ is alkylor aryl, can be prepared by reacting IP⁺(OR⁶)₃ with mono-protected diolsX according to the procedure described in Stowell et al., 1995,Tetrahedron Lett. 36:11, 1825 or by alkylation of protected haloalcohols 14 with the appropriate dialkyl or diaryl phosphates (see e.g.,Okamoto, 1985, Bull Chem. Soc. Jpn. 58:3393, hereby expresslyincorporated herein by reference).

Protected alcohols 16 wherein Y comprises a diphosphate group of theformula

wherein R⁶ is defined as above, can be synthesized by reacting theabove-discussed monophosphates of the formula:

with a phosphate of the formula

(commercially available, e.g., Aldrich Chemical Co., Milwaukee, Wis.),in the presence of carbodiimide such as dicyclohexylcarbodiimide, asdescribed in Houben-Weyl, Methoden der Organische Chemie, Georg ThiemeVerlag Stuttgart 1964, vol. XII/2, pp. 881-885. In the same fashion,protected alcohols 16, wherein Y comprises a triphosphate group of theformula:

can be synthesized by reacting the above-discussed diphosphate protectedalcohols, of the formula:

with a phosphate of the formula:

as described above. Alternatively, when R⁶ is H, protected alcohols 16wherein Y comprises the triphosphate group, can be prepared by reactingmono-protected diols X with salicyl phosphorochloridite and thenpyrophosphate and subsequent cleavage of the adduct thus obtained withiodine in pyridine as described in Ludwig et al., 1989, J. Org. Chem.54:631, hereby expressly incorporated herein by reference.

Protected alcohols 16, wherein Y is —SO₃H or a heterocyclic groupselected from the group consisting of:

can be prepared by halide displacement from protected halo-alcohols 14.Thus, when Y is —SO₃H, protected alcohols 16 can by synthesized byreacting protected halo-alcohols 14 with sodium sulfite as described inGilbert Sulfonation and Related Reactions; Wiley: New York, 1965, pp.136-148 and pp. 161-163; Org. Synth. Coll. Vol. I, Wiley, NY, 558, 564(1943); and Org. Synth. Coll. Vol. IV, Wiley, NY, 529 (1963), all threeof which are hereby expressly incorporated herein by reference. When Yis one of the above-mentioned heterocycles, protected alcohols 16 can beprepared by reacting protected halo-alcohols 14 with the correspondingheterocycle in the presence of a base. The heterocycles are availablecommercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or preparedby well-known synthetic methods (see the procedures described in Ware,1950, Chem. Rev. 46:403-470, hereby expressly incorporated herein byreference). Preferably, the reaction is conducted by stirring a mixturecomprising 14, the heterocycle, and a solvent at a constant temperaturewithin the range of about room temperature to about 100° C., preferablywithin the range of about 50° C. to about 70° C. for about 10 to about48 hours. Suitable bases include hydroxide bases such as sodiumhydroxide, potassium hydroxide, sodium carbonate, or potassiumcarbonate. Preferably, the solvent used in forming protected alcohols 16is selected from dimethylformamide; formamide; dimethyl sulfoxide;alcohols, such as methanol or ethanol; and mixtures thereof. Theprogress of the reaction can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography and when substantially complete, theproduct can be isolated by workup and purified if desired.

Protected alcohols 16, wherein Y is a heteroaryl ring selected from

can be prepared by metallating the suitable heteroaryl ring thenreacting the resulting metallated heteroaryl ring with protectedhalo-alcohols 14 (for a review, see Katritzky Handbook of HeterocyclicChemistry, Pergamon Press: Oxford 1985). The heteroaryl rings areavailable commercially or prepared by well-known synthetic methods (seee.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo etal., 1971, J. Chem. Soc. (C) 86; Oster et al., 1983, J. Org. Chem.48:4307; Iwai et al., 1966, Chem. Pharm. Bull. 14:1277; and U.S. Pat.No. 3,152,148, all of which citations are hereby expressly incorporatedherein by reference). As used herein, the term “metallating” means theforming of a carbon-metal bond, which bond may be substantially ionic incharacter. Metallation can be accomplished by adding about 2 equivalentsof strong organometallic base, preferably with a pK_(a) of about 25 ormore, more preferably with a pK_(a) of greater than about 35, to amixture comprising a suitable organic solvent and the heterocycle. Twoequivalents of base are required: one equivalent of the basedeprotonates the —OH group or the —NH group, and the second equivalentmetallates the heteroaryl ring. Alternatively, the hydroxy group of theheteroaryl ring can be protected with a base-stable, acid-labileprotecting group as described in Greene, T. W., Protective Groups inOrganic Synthesis, 3rd edition 17-237 (1999), hereby expresslyincorporated herein by reference. Where the hydroxy group is protected,only one equivalent of base is required. Examples of suitablebase-stable, acid-labile hydroxyl-protecting groups, include but are notlimited to, ethers, such as methyl, methoxy methyl, methylthiomethyl,methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,o-nitrobenzyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly straight chain ethers, such as methyl ether,methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether,bis(2-chloroethoxy)methyl ether. Preferably, the pK_(a) of the base ishigher than the pK_(a) of the proton of the heterocycle to bedeprotonated. For a listing of pK_(a)s for various heteroaryl rings, seeFraser et al., 1985, Can. J. Chem. 63:3505, hereby expresslyincorporated herein by reference. Suitable bases include, but are notlimited to, alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride. If desired,the organometallic base can be activated with a complexing agent, suchas N,N,N′,N′-tetramethylethylenediamine or hexamethylphosphoramide(1970, J. Am. Chem. Soc. 92:4664, hereby expressly incorporated hereinby reference). Solvents suitable for synthesizing protected alcohols 16,wherein Y is a heteroaryl ring include, but are not limited to, diethylether; tetrahydrofuran; and hydrocarbons, such as pentane. Generally,metallation occurs alpha to the heteroatom due to the inductive effectof the heteroatom, however, modification of conditions, such as theidentity of the base and solvents, order of reagent addition, reagentaddition times, and reaction and addition temperatures can be modifiedby one of skill in the art to achieve the desired metallation position(see e.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, pp.30-42, hereby expressly incorporated herein by reference) Alternatively,the position of metallation can be controlled by use of a halogenatedheteroaryl group, wherein the halogen is located on the position of theheteroaryl ring where metallation is desired (see e.g., Joule et al.,Heterocyclic Chemistry, 3rd ed., 1995, p. 33 and Saulnier et al., 1982,J. Org. Chem. 47:757, the two of which citations are hereby expresslyincorporated herein by reference). Halogenated heteroaryl groups areavailable commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) orcan be prepared by well-known synthetic methods (see e.g., Joule et al.,Heterocyclic Chemistry, 3rd ed., 1995, pp. 78, 85, 122, 193, 234, 261,280, 308, hereby expressly incorporated herein by reference). Aftermetallation, the reaction mixture comprising the metallated heteroarylring is adjusted to within a temperature range of about 0° C. to aboutroom temperature and protected halo-alcohols 14 (diluted with a solventor in undiluted form) are added, preferably at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. After addition of protectedhalo-alcohols 14, the reaction mixture is stirred at a constanttemperature within the range of about room temperature and about thesolvent's boiling temperature and the reaction's progress can bemonitored by the appropriate analytical technique, preferably thin-layerchromatography or high-performance liquid chromatography. After thereaction is substantially complete, protected alcohols 16 can beisolated by workup and purification. It is to be understood thatconditions, such as the identity of protected halo-alcohol 14, the base,solvents, orders of reagent addition, times, and temperatures, can bemodified by one of skill in the art to optimize the yield andselectivity. Exemplary procedures that can be used in such atransformation are described in Shirley et al., 1995, J. Org. Chem.20:225; Chadwick et al., 1979, J. Chem. Soc., Perkin Trans. 1 2845;Rewcastle, 1993, Adv. Het. Chem. 56:208; Katritzky et al., 1993, Adv.Het. Chem. 56:155; and Kessar et al., 1997, Chem. Rev. 97:721.When Y is

protected alcohols 16 can be prepared from their correspondingcarboxylic acid derivatives (16, wherein Y is —CO₂H) as described inBelletire et al, 1988, Synthetic Commun. 18:2063 or from thecorresponding acylchlorides (16, wherein Y is —CO-halo) as described inSkinner et al., 1995, J. Am. Chem. Soc. 77:5440, both citations arehereby expressly incorporated herein by reference. The acylhalides canbe prepared from the carboxylic acids by well known procedures such asthose described in March, J., Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, pp. 437-438, hereby expresslyincorporated herein by reference. When Y is

wherein R⁷ is as defined above, protected alcohols 16 can be prepared byfirst reacting protected halo-alcohols 15 with a trialkyl phosphiteaccording to the procedure described in Kosolapoff, 1951, Org. React.6:273 followed by reacting the derived phosphonic diester with ammoniaaccording to the procedure described in Smith et al., 1957, J. Org.Chem. 22:265, hereby expressly incorporated herein by reference. When Yis

protected alcohols 16 can be prepared by reacting their sulphonic acidderivatives (i.e., 16, wherein Y is —SO₃H ) with ammonia as described inSianesi et al., 1971, Chem. Ber. 104:1880 and Campagna et al., 1994,Farmaco, Ed. Sci. 49:653, both of which citations are hereby expresslyincorporated herein by reference).

As further illustrated in Scheme 2, protected alcohols 16 can bedeprotected providing alcohols 20a. The deprotection method depends onthe identity of the alcohol-protecting group, see e.g., the procedureslisted in Greene, T. W., Protective Groups in Organic Synthesis, 3rdedition 17-237 (1999), particularly see pages 48-49, hereby expresslyincorporated herein by reference. One of skill in the art will readilybe able to choose the appropriate deprotection procedure. When thealcohol is protected as an ether function (e.g., methoxymethyl ether),the alcohol is preferably deprotected with aqueous or alcoholic acid.Suitable deprotection reagents include, but are not limited to, aqueoushydrochloric acid, p-toluenesulfonic acid in methanol,pyridinium-p-toluenesulfonate in ethanol, Amberlyst H-15 in methanol,boric acid in ethylene-glycol-monoethylether, acetic acid in awater-tetrahydrofuran mixture, aqueous hydrochloric acid is preferred.Examples of such procedures are described, respectively, in Bemady etal., 1979, J. Org. Chem. 44:1438; Miyashita et al., 1977, J. Org. Chem.42:3772; Johnston et al., 1988, Synthesis 393; Bongini et al., 1979,Synthesis 618; and Hoyer et al., 1986, Synthesis 655; Gigg et al., 1967,J. Chem. Soc. C, 431; and Corey et al., 1978, J. Am. Chem. Soc.100:1942, all of which are hereby expressly incorporated herein byreference.

Scheme 3 depicts the synthesis of protected lactone alcohols 20 andlactone alcohols 13a. Compounds 20 and 13a correspond to compounds ofthe formula W⁽¹⁾⁽²⁾⁻Zm-OPG and W⁽¹⁾⁽²⁾⁻Z_(m-)OH respectively, whereinW⁽¹⁾⁽²⁾ is a lactone group selected from:

Protected lactone alcohols 20 can be prepared from compounds of theformula 17, 18, or 19 by using well-known condensation reactions andvariations of the Michael reaction. Methods for the synthesis oflactones are disclosed in Multzer in Comprehensive Organic FunctionalGroup Transformations, A. R. Katritzky, O. Meth-Cohn and C. W. Rees,Eds. Pergamon: Oxford, 1995, vol 5, pp. 161-173, hereby expresslyincorporated herein by reference. Mono-protected diols 19, electrophilicprotected alcohols 18, and aldehydes 19 are readily available ethercommercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) or by wellknown synthetic procedures.

When W⁽¹⁾⁽²⁾ is a beta-lactone group of the formula:

protected lactone alcohols 20 can be prepared from aldehydes 19 andelectrophilic protected alcohols 18, respectively, by aone-pot-addition-lactonization according to the procedure of Masamune etal., 1976, J. Am. Chem. Soc. 98:7874 and Danheiser et al., 1991, J. Org.Chem. 56:1176, both of which are hereby expressly incorporated herein byreference. This one-pot-addition-lactonization methodology has beenreviewed by Multzer in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds.Pergamon: Oxford, 1995, vol 5, pp. 161, hereby expressly incorporatedherein by reference When W⁽¹⁾⁽²⁾ is a gamma- or delta-lactone group ofthe formula:

protected lactone alcohols 20 can be prepared from aldehydes 19according to well known synthetic methodology. For example, themethodology described in Masuyama et al., 2000, J. Org. Chem. 65:494;Eisch et al., 1978, J. Organo. Met. Chem. C8 160; Eaton et al., 1947, J.Org. Chem. 37:1947; Yunker et al., 1978, Tetrahedron Lett. 4651; Bhanotet al., 1977, J. Org. Chem. 42:1623; Ehlinger et al., 1980, J. Am. Chem.Soc. 102:5004; and Raunio et al., 1957, J. Org. Chem. 22:570, all ofwhich citations are hereby expressly incorporated herein by reference.For instance, as described in Masuyama et al., 2000, J. Org. Chem.65:494, aldehydes 19 can be treated with about 1 equivalent of a strongorganometallic base, preferably with a pK_(a) of about 25 or more, morepreferably with a pK_(a) of greater than about 35, in a suitable organicsolvent to give a reaction mixture. Suitable bases include, but are notlimited to, alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Suitable solvents include, but are notlimited to, diethyl ether and tetrahydrofuran. The reaction-mixturetemperature is adjusted to within the range of about 0° C. to about 100°C., preferably about room temperature to about 50° C., and a halide ofthe formula:

wherein z is 1 or 2 (diluted with a solvent or in undiluted form) isadded. The reaction mixture is stirred for a period of about 2 hours toabout 48 hours, preferably about 5 to about 10 hours, during which timethe reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, protected lactone alcohols 20 can be isolated byworkup and purified if desired. When W⁽¹⁾⁽²⁾ is a gamma- ordelta-lactone group of the formula:

protected lactone alcohols 20 can be synthesized by deprotonating thecorresponding lactone with a strong base providing the lactone enolateand reacting the enolate with electrophilic protected alcohols 20 (for adetailed discussion of enolate formation of active methylene compoundssuch as lactones, see House Modern Synthetic Reactions; W. A. Benjamin,Inc. Philippines 1972 pp. 492-570, and for a discussion of reaction oflactone enolates with electrophiles such as carbonyl compounds, seeMarch, J. Advanced Organic Chemistry; Reactions Mechanisms andStructure, 4th ed., 1992, pp. 944-945, both of which are herebyexpressly incorporated herein by reference). Lactone-enolate formationcan be accomplished by adding about 1 equivalent of a strongorganometallic base, preferably with a pK_(a) of about 25 or more, morepreferably with a pK_(a) of greater than about 35, to a mixturecomprising a suitable organic solvent and the lactone. Suitable basesinclude, but are not limited to, alkylmetal bases such as methyllithium,n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium,phenyl sodium, and phenyl potassium; metal amide bases such as lithiumamide, sodium amide, potassium amide, lithium tetramethylpiperidide,lithium diisopropylamide, lithium diethylamide, lithiumdicyclohexylamide, sodium hexamethyldisilazide, and lithiumhexamethyldisilazide; and hydride bases such as sodium hydride andpotassium hydride, preferably lithium tetramethylpiperidide. Solventssuitable for lactone-enolate formation include, but are not limited to,diethyl ether and tetrahydrofuran. After enolate formation, thereaction-mixture temperature is adjusted to within the range of about−78° C. to about room temperature, preferably about −50° C. to about 0°C., and electrophilic protected alcohols 18 (diluted with a solvent orin undiluted form) are added, preferably at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. The reaction mixture isstirred for a period of about 15 minutes to about 5 hours, during whichtime the reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, protected lactone alcohols 20 can be isolated byworkup and purified if desired. When W⁽¹⁾⁽²⁾ is a lactone group of theformula:

protected lactone alcohols 20 can be prepared from aldehydes 19according to the procedure described in U.S. Pat. No. 4,622,338, herebyexpressly incorporated herein by reference.

When W⁽¹⁾⁽²⁾ is a gamma- or delta-lactone group of the formula:

protected lactone alcohols 20 can be prepared according to a three stepsequence. The first step comprises base-mediated reaction ofelectrophilic protected alcohols 18 with succinic acid esters (i.e.,R⁹O₂CCH₂CH₂CO₂R⁹, wherein R⁹ is alkyl) or glutaric acid esters (i.e.,R⁹O₂CCH₂CH₂CH₂CO₂R⁹, wherein R⁹ is alkyl) providing a diesterintermediate of the formula 21:

wherein x is 1 or 2 depending on whether the gamma or delta lactonegroup is desired. The reaction can be performed by adding about 1equivalent of a strong organometallic base, preferably with a pK_(a) ofabout 25 or more, more preferably with a pK_(a) of greater than about35, to a mixture comprising a suitable organic solvent and the succinicor glutaric acid ester. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Suitable solvents include, but are notlimited to, diethyl ether and tetrahydrofuran. After enolate formation,the reaction-mixture temperature is adjusted to within the range ofabout −78° C. to about room temperature, preferably about −50° C. toabout 0° C., and electrophilic protected alcohols 18 (diluted with asolvent or in undiluted form) are added, preferably at a rate such thatthe reaction-mixture temperature remains within about one to two degreesof the initial reaction-mixture temperature. The reaction mixture isstirred for a period of about 15 minutes to about 5 hours, during whichtime the reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, the diester intermediate be isolated by workupand purified if desired. In the second step, the intermediate diestercan be reduced, with a hydride reducing agent, to yield a diol of theformula 22:

The reduction can be performed according to the procedures referenced inMarch, J. Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, p. 1214, hereby expressly incorporated hereinby reference). Suitable reducing agents include, but are not limited to,lithium aluminum hydride, diisobutylaluminum hydride, sodiumborohydride, and lithium borohydride). In the third step, the diol canbe oxidatively cyclized with RuH₂(PPh₃)₄ to the product protectedlactone alcohols 20 according to the procedure of Yoshikawa et al.,1986, J. Org. Chem. 51:2034 and Yoshikawa et al., 1983, TetrahedronLett. 26:2677, both of which citations are hereby expressly incorporatedherein by reference. When W⁽¹⁾⁽²⁾ is a lactone group of the formula:

protected lactone alcohols 20 can be synthesized by reacting theGrignard salts of electrophilic protected alcohols 18, where E is ahalide, with 5,6-dihydro-2H-pyran-2-one, commercially available (e.g.,Aldrich Chemical Co., Milwaukee, Wis.), in the presence of catalyticamounts of a1-dimethylaminoacetyl)pyrolidine-2yl)methyl-diarylphosphine-copper(I)iodide complex as described in Tomioka et al., 1995, Tetrahedron Lett.36:4275, hereby expressly incorporated herein by reference.

Scheme 4 outlines methodology for the synthesis of protected alcohols14. Compounds 14, wherein n is an integer ranging from 1 to 5, can beprepared from compounds 11 using general synthetic strategy depicted andadapting the synthetic protocols from those discussed for Scheme 1.

Next, Scheme 4 depicts the general strategy for the synthesis ofcompounds 14 wherein n is 0. First, Esters 27, wherein R⁸ is as definedabove, are synthesized by oxidation of mono-protected diols X in thepresence of R⁸OH (see generally, March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992, p. 1196). Anexemplary procedure for such an oxidation is described in Stevens etal., 1982, Tetrahedron Lett. 23:4647 (HOCl); Sundararaman et al., 1978,Tetrahedron Lett. 1627 (O₃/KOH); Wilson et al., 1982, J. Org. Chem.47:1360 (t-BuOOH/Et₃N); and Williams et al., 1988, Tetrahedron Lett.29:5087 (Br₂), the four of which citations are hereby expresslyincorporated herein by reference. Compounds 28 are converted tocompounds 14 wherein n is 0 by adapting the synthetic proceduresdepicted in Scheme 1.

Scheme 5 outlines methodology for the synthesis of protected alcohols 29and alcohols 15a, which correspond to W⁽¹⁾⁽²⁾⁻Z_(m-)OPG andW⁽¹⁾⁽²⁾⁻Z_(m-)OH, respectively, wherein W⁽¹⁾⁽²⁾ isC(R¹)(R²)—(CH₂)_(c)C(R³)(R⁴)—Y. The synthesis of starting materials 14,26, and 28 are depicted in Scheme 4 and the synthetic methods andprocedures can be adapted from those described for Scheme 2.

Scheme 6 depicts the synthesis of protected lactone alcohols 30 andlactone alcohols 16a. Compounds 30 and 16a correspond to compounds ofthe formula, which correspond to compounds W⁽¹⁾⁽²⁾⁻Z_(m-)OH, WhereinW⁽¹⁾⁽²⁾ is C(R¹)(R²)(CH2)_(c-)V and V is a Group selected from:

As shown in Scheme 6, protected lactone alcohols 30 and lactone alcohols16a can be synthesized from compounds of the formula X, 11, or 12 byadaptation of the methods and procedures discussed above for Scheme 3.

Scheme 7 depicts the synthesis of halides 17. Halides 17 can besynthesized by a variety of methods. One method involves conversion ofthe alcohol to a leaving group such as a sulfonic ester, such as, forexample, tosylate, brosylate, mesylate, or nosylate. This intermediateis then treated with a source of X⁻, wherein X⁻ is I⁻, Br⁻, or Cl⁻ in asolvent such as THF or ether. A general method for converting vinyl andphenyl alcohols to thiols involves initially converting the alcohol to aleaving group (e.g., a tosylate) then treating with a halidenucleophile.

Scheme 8 outlines the synthesis of compounds I. In the first step,compounds I are synthesized by reacting compounds 17 (compounds X 11,12, 13, 14, 15, and 16 are encompassed by 17) with compounds 31 underthe conditions suitable for the formation of compounds I. The conditionsand methods discussed in Scheme 1 above for the synthesis ofmono-protected diols X from alcohols 6 can be adapted for the synthesisof compounds 17. Compounds 31, wherein Y is a suitable leaving group asdefined above, preferably an anhydride, an ester, or an amide group, arereadily obtained commercially (e.g., Aldrich Chemical Co. MilwaukeeWis.) or by well known synthetic methods. Compounds I are obtained byreacting compounds 31 with compounds 17 under the conditions suitablefor alkyl-de-acyloxy substitution. (For a review, See Kharasch;Reinmuth, Grignard Reactions of Nonmetallic Substances; Prentice Hall:Englewood Cliffs, N.J., 1954, pp. 561-562 and 846-908. In a preferredprocedure, the conversion of anhydrides, carboxylic esters, or amides toketones with organometallic compounds. In a particular procedure,anhydrides and carboxylic esters give ketones when treated using inverseaddition of Grignard reagents at low temperature with the solvent HMPA.See Newman, J. Org. Chem. 1948, 13, 592; Huet; Empotz; JubierTetrahedron 1973, 29, 479; and Comprehensive Organic Transformations;VCH: New York, 1989, pp. 685-686, 693-700. Ketones can also be prepareby the treatment of thioamides with organolithium compounds (alkyl oraryl). See Tominaga; Kohra; Hosomi Tetrahedron Lett. 1987, 28, 1529.Moreover, alkyllithium compounds have been used to give ketones fromcarboxylic esters. See Petrov; Kaplan; Tsir J. Gen. Chem. USSR 1962, 32,691. The reaction must be carried out in a high-boiling solvent such astoluene. Di-substituted amides also can be used to synthesize ketones.See Evans J. Chem. Soc. 1956, 4691; and Wakefield Organolithium Methods;Academic Press: New York, 1988, pp. 82-88.

Scheme 9 illustrates the alpha disubstitution of an ester containing aterminal protected hydroxyl moiety. Compounds that contain strongelectron withdrawing groups are easily converted to the correspondingenolates. These enolate ions can readilt attack an electrophileresulting in alpha substitution. See Some Modern Methods of OrganicSynthesis, 3^(rd) Ed.; Cambridge University Press: Cambridge, 1986, pp.1-26, hereby expressly incorporated herein by reference. The reaction issuccessful for primary and secondary alkyl, allylic, and benzylic. Theuse of polar aprotic solvents, e.g., dimethylformamide ordimethylsulfoxide, are preferred. Phase transfer catalysts can also beused. See Tundo et al. J. Chem. Soc., Perkin Trans. 1, 1987, 2159, whichis hereby expressly incorporated herein by reference.

The conversion to a carboxylic acid with an additional carbon isachieved by treating an acyl halide with diazomethane to generate anintermediate diazo ketone, which in the presence of water and silveroxide rearranges through a ketene intermediate to a carboxylic acid withan additional carbon atom 37. If the reaction is done in an alcoholinstead of water an ester is recovered. See Meier et al. Angew. Chem.Int. Ed. Eng. 1975, 14, 32-43, which is hereby expressly incorporatedherein by reference. Alternatively, the carboxylic acid can beesterified by known techniques. The reaction can be repeated to generatemethylene groups adjacent to the carboxylic acid.

Scheme 10 outlines methodology for the synthesis of protected alcohols42a wherein Y, R¹, R², Z, and m are defined as above. Protected alcohols42a correspond to compounds of the formula W⁽¹⁾⁽²⁾⁻Z_(m-)OPG, whereinW⁽¹⁾⁽²⁾ is C(R¹)(R²)—Y.

Protected alcohols 42, wherein Y comprises a —C(O)OH group, can besynthesized by oxidizing mono-protected diols 39 with an agent suitablefor oxidizing a primary alcohol to a carboxylic acid (for a discussionsee M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186,1990, pp. 127-130, hereby expressly incorporated herein by reference).Suitable oxidizing agents include, but are not limited to, pyridiniumdichromate (Corey et al., 1979, Tetrahedron Lett. 399); manganesedioxide (Ahrens et al., 1967, J. Heterocycl. Chem. 4:625); sodiumpermanganate monohydrate (Menger et al., 1981, Tetrahedron Lett.22:1655); and potassium permanganate (Sam et al., 1972, J. Am. Chem.Soc. 94:4024), all of which citations are hereby expressly incorporatedherein by reference. The preferred oxidizing reagent is pyridiniumdichromate. In an alternative synthetic procedure, protected alcohols42, wherein Y comprises a —C(O)OH group, can be synthesized by treatmentof protected halo-alcohols 40, wherein X is iodo, with CO or CO₂, asdescribed in Bailey et al., 1990, J. Org. Chem. 55:5404 and Yanagisawaet al., 1994, J. Am. Chem. Soc. 116:6130, the two of which citations arehereby expressly incorporated herein by reference. Protected alcohols42, wherein Y comprises —C(O)OR⁵, wherein R⁵ is as defined above, can besynthesized by oxidation of mono-protected diols 39 in the presence ofR⁵OH (see generally, March, J. Advanced Organic Chemistry; ReactionsMechanisms, and Structure, 4th ed., 1992, p. 1196). An exemplaryprocedure for such an oxidation is described in Stevens et al., 1982,Tetrahedron Lett. 23:4647 (HOCl); Sundararaman et al., 1978, TetrahedronLett. 1627 (O₃/KOH); Wilson et al., 1982, J. Org. Chem. 47:1360(t-BuOOH/Et₃N); and Williams et al., 1988, Tetrahedron Lett. 29:5087(Br₂), the four of which citations are hereby expressly incorporatedherein by reference. Preferably, protected alcohols 42, wherein Ycomprises a —C(O)OR⁵ group are synthesized from the correspondingcarboxylic acid (i.e., 42, wherein Y comprises —C(O)OH) byesterification with R⁵OH (e.g., see March, J., Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p.393-394, hereby expressly incorporated herein by reference). In anotheralternative synthesis, protected alcohols 42, wherein Y comprises—C(O)OR⁵, can be prepared from protected halo-alcohols 40 bycarbonylation with transition metal complexes (see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 484-486; Urata et al., 1991, Tetrahedron Lett. 32:36,4733); and Ogata et al., 1969, J. Org. Chem. 3985, the three of whichcitations are hereby expressly incorporated herein by reference).

Protected alcohols 42, wherein Y comprises —OC(O)R⁵, wherein R⁵ is asdefined above, can be prepared by acylation of mono-protected diols 39with a carboxylate equivalent such as an acyl halide (i.e., R⁵C(O)-Hal,wherein Hal is iodo, bromo, or chloro, see e.g., March, J. AdvancedOrganic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992,p. 392 and Org. Synth. Coll. Vol. III, Wiley, NY, pp. 142, 144, 167, and187 (1955)) or an anhydride (i.e., R⁵C(O)—O—(O)CR⁵, see e.g., March, J.Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, p. 392-393 and Org. Synth. Coll. Vol. III, Wiley, NY, pp. 11,127, 141, 169, 237, 281, 428, 432, 690, and 833 (1955), all of whichcitations are incorporated herein by reference). Preferably, thereaction is conducted by adding a base to a solution comprisingmono-protected diols 39, a carboxylate equivalent, and an organicsolvent, which solution is preferably maintained at a constanttemperature within the range of 0° C. to about room temperature.Solvents suitable for reacting mono-protected diols 39 with acarboxylate equivalent include, but are not limited to, dichloromethane,toluene, and ether, preferably dichloromethane. Suitable bases include,but are not limited to, hydroxide sources, such as sodium hydroxide,potassium hydroxide, sodium carbonate, or potassium carbonate; or anamine such as triethylamine, pyridine, or dimethylaminopyridine, aminesare preferred. The progress of the reaction can be followed by using anappropriate analytical technique, such as thin layer chromatography orhigh performance liquid chromatography and when substantially complete,the product can be isolated by workup and purified if desired.

Protected alcohols 42, wherein Y comprises one of the followingphosphate ester groups

wherein R⁶ is defined as above, can be prepared by phosphorylation ofmono-protected diols X according to well-known methods (for a generalreviews, see Corbridge Phosphorus: An Outline of its Chemistry,Biochemistry, and Uses, Studies in Inorganic Chemistry, 3rd ed., pp.357-395 (1985); Ramirez et al., 1978, Acc. Chem. Res. 11:239; andKalckare Biological Phosphorylations, Prentice-Hall, New York (1969); J.B. Sweeny in Comprehensive Organic Functional Group Transformations, A.R. Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon: Oxford, 1995,vol 2, pp. 104-109, the four of which are hereby expressly incorporatedherein by reference). Protected alcohols 42 wherein Y comprises amonophosphate group of the formula:

wherein R⁶ is defined as above, can be prepared by treatment ofmono-protected diol 39 with phosphorous oxychloride in a suitablesolvent, such as xylene or toluene, at a constant temperature within therange of about 100° C. to about 150° C. for about 2 hours to about 24hours. After the reaction is deemed substantially complete, by using anappropriate analytical method, the reaction mixture is hydrolyzed withR⁶⁻OH. Suitable procedures are referenced in Houben-Weyl, Methoden derOrganische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2, pp.143-210 and 872-879, hereby expressly incorporated herein by reference.Alternatively, when both R⁶ are hydrogen, can be synthesized by reactingmono-protected diols X with silyl polyphosphate (Okamoto et al., 1985,Bull Chem. Soc. Jpn. 58:3393, hereby expressly incorporated herein byreference) or by hydrogenolysis of their benzyl or phenyl esters (Chenet al., 1998, J. Org. Chem. 63:6511, incorporated herein by reference).In another alternative procedure, when R⁶ is (C₁₋C₆)alkyl,(C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl, the monophosphate esters can beprepared by reacting mono-protected diols 39 with appropriatelysubstituted phophoramidites followed by oxidation of the intermediatewith m-chloroperbenzoic acid (Yu et al., 1988, Tetrahedron Lett. 29:979,incorporated herein by reference) or by reacting mono-protected diols 39with dialkyl or diaryl substituted phosphorochloridates (Pop, et al,1997, Org. Prep. and Proc. Int. 29:341, incorporated herein byreference). The phosphoramidites are commercially available (e.g.,Aldrich Chemical Co., Milwaukee, Wis.) or readily prepared according toliterature procedures (see e.g., Uhlmann et al.1986, Tetrahedron Lett.27:1023 and Tanaka et al., 1988, Tetrahedron Lett. 29:199, both of whichare incorporated herein by reference). The phosphorochloridates are alsocommercially available (e.g., Aldrich Chemical Co., Milwaukee, Wis.) orprepared according to literature methods (e.g., Gajda et al, 1995,Synthesis 25:4099. In still another alternative synthesis, protectedalcohols 42, wherein Y comprises a monophosphate group and R⁶ is alkylor aryl, can be prepared by reacting IP⁺(OR⁶)₃ with mono-protected diols39 according to the procedure described in Stowell et al., 1995,Tetrahedron Lett. 36:11, 1825 or by alkylation of protected haloalcohols 40 with the appropriate dialkyl or diaryl phosphates (see e.g.,Okamoto, 1985, Bull Chem. Soc. Jpn. 58:3393, incorporated herein byreference).

Protected alcohols 42 wherein Y comprises a diphosphate group of theformula

wherein R⁶ is defined as above, can be synthesized by reacting theabove-discussed monophosphates of the formula:

with a phosphate of the formula

(commercially available, e.g., Aldrich Chemical Co., Milwaukee, Wis.),in the presence of carbodiimide such as dicyclohexylcarbodiimide, asdescribed in Houben-Weyl, Methoden der Organische Chemie, Georg ThiemeVerlag Stuttgart 1964, vol. XII/2, pp. 881-885. In the same fashion,protected alcohols 42, wherein Y comprises a triphosphate group of theformula:

can be synthesized by reacting the above-discussed diphosphate protectedalcohols, of the formula:

with a phosphate of the formula:

as described above. Alternatively, when R⁶ is H, protected alcohols 42wherein Y comprises the triphosphate group, can be prepared by reactingmono-protected diols 39 with salicyl phosphorochloridite and thenpyrophosphate and subsequent cleavage of the adduct thus obtained withiodine in pyridine as described in Ludwig et al., 1989, J. Org. Chem.54:631, incorporated herein by reference.

Protected alcohols 42, wherein Y is —SO₃H or a heterocyclic groupselected from the group consisting of:

can be prepared by halide displacement from protected halo-alcohols 40.Thus, when Y is —SO₃H, protected alcohols 42 can by synthesized byreacting protected halo-alcohols 40 with sodium sulfite as described inGilbert Sulfonation and Related Reactions; Wiley: New York, 1965, pp.136-148 and pp. 161-163; Org. Synth. Coll. Vol. II, Wiley, NY, 558, 564(1943); and Org. Synth. Coll. Vol. IV, Wiley, NY, 529 (1963), all threeof which are incorporated herein by reference. When Y is one of theabove-mentioned heterocycles, protected alcohols 42 can be prepared byreacting protected halo-alcohols 40 with the corresponding heterocyclein the presence of a base. The heterocycles are available commercially(e.g., Aldrich Chemical Co., Milwaukee, Wis.) or prepared by well-knownsynthetic methods (see the procedures described in Ware, 1950, Chem.Rev. 46:403-470, incorporated herein by reference). Preferably, thereaction is conducted by stirring a mixture comprising 40, theheterocycle, and a solvent at a constant temperature within the range ofabout room temperature to about 100° C., preferably within the range ofabout 50° C. to about 70° C. for about 10 to about 48 hours. Suitablebases include hydroxide bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, or potassium carbonate. Preferably, thesolvent used in forming protected alcohols 42 is selected fromdimethylformamide; formamide; dimethyl sulfoxide; alcohols, such asmethanol or ethanol; and mixtures thereof. The progress of the reactioncan be followed by using an appropriate analytical technique, such asthin layer chromatography or high performance liquid chromatography andwhen substantially complete, the product can be isolated by workup andpurified if desired.

Protected alcohols 42, wherein Y is a heteroaryl ring selected from

can be prepared by metallating the suitable heteroaryl ring thenreacting the resulting metallated heteroaryl ring with protectedhalo-alcohols 40 (for a review, see Katritzky Handbook of HeterocyclicChemistry, Pergamon Press: Oxford 1985). The heteroaryl rings areavailable commercially or prepared by well-known synthetic methods (seee.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995; De Sarlo etal., 1971, J. Chem. Soc. (C) 86; Oster et al., 1983, J. Org. Chem.48:4307; Iwai et al., 1966, Chem. Pharm. Bull. 14:1277; and U.S. Pat.No. 3,152,148, all of which citations are incorporated herein byreference). As used herein, the term “metallating” means the forming ofa carbon-metal bond, which bond may be substantially ionic in character.Metallation can be accomplished by adding about 2 equivalents of strongorganometallic base, preferably with a pK_(a) of about 25 or more, morepreferably with a pK_(a) of greater than about 35, to a mixturecomprising a suitable organic solvent and the heterocycle. Twoequivalents of base are required: one equivalent of the basedeprotonates the —OH group or the —NH group, and the second equivalentmetallates the heteroaryl ring. Alternatively, the hydroxy group of theheteroaryl ring can be protected with a base-stable, acid-labileprotecting group as described in Greene, T. W., Protective Groups inOrganic Synthesis, 3rd edition 17-237 (1999), hereby expresslyincorporated herein by reference. Where the hydroxy group is protected,only one equivalent of base is required. Examples of suitablebase-stable, acid-labile hydroxyl-protecting groups, include but are notlimited to, ethers, such as methyl, methoxy methyl, methylthiomethyl,methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahyrofuranyl, tetrahydrothiofuranyl,1-ethoxyethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl,o-nitrobenzyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl,trimethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl; and esters,such as pivaloate, adamantoate, and 2,4,6-trimethylbenzoate. Ethers arepreferred, particularly straight chain ethers, such as methyl ether,methoxymethyl ether, methylthiomethyl ether, methoxyethoxymethyl ether,bis(2-chloroethoxy)methyl ether. Preferably, the pK_(a) of the base ishigher than the pK_(a) of the proton of the heterocycle to bedeprotonated. For a listing of pK_(a)s for various heteroaryl rings, seeFraser et al., 1985, Can. J. Chem. 63:3505, incorporated herein byreference. Suitable bases include, but are not limited to, alkylmetalbases such as methyllithium, n-butyllithium, tert-butyllithium,sec-butyllithium, phenyllithium, phenyl sodium, and phenyl potassium;metal amide bases such as lithium amide, sodium amide, potassium amide,lithium tetramethylpiperidide, lithium diisopropylamide, lithiumdiethylamide, lithium dicyclohexylamide, sodium hexamethyldisilazide,and lithium hexamethyldisilazide; and hydride bases such as sodiumhydride and potassium hydride. If desired, the organometallic base canbe activated with a complexing agent, such asN,N,N′,N′-tetramethylethylenediamine or hexamethylphosphoramide (1970,J. Am. Chem. Soc. 92:4664, hereby expressly incorporated herein byreference). Solvents suitable for synthesizing protected alcohols 42,wherein Y is a heteroaryl ring include, but are not limited to, diethylether; tetrahydrofuran; and hydrocarbons, such as pentane. Generally,metallation occurs alpha to the heteroatom due to the inductive effectof the heteroatom, however, modification of conditions, such as theidentity of the base and solvents, order of reagent addition, reagentaddition times, and reaction and addition temperatures can be modifiedby one of skill in the art to achieve the desired metallation position(see e.g., Joule et al., Heterocyclic Chemistry, 3rd ed., 1995, pp.30-42, hereby expressly incorporated herein by reference) Alternatively,the position of metallation can be controlled by use of a halogenatedheteroaryl group, wherein the halogen is located on the position of theheteroaryl ring where metallation is desired (see e.g., Joule et al.,Heterocyclic Chemistry, 3rd ed., 1995, p. 33 and Saulnier et al., 1982,J. Org. Chem. 47:757, the two of which citations are hereby expresslyincorporated herein by reference). Halogenated heteroaryl groups areavailable commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.) orcan be prepared by well-known synthetic methods (see e.g., Joule et al.,Heterocyclic Chemistry, 3rd ed., 1995, pp. 78, 85, 122, 193, 234, 261,280, 308, hereby expressly incorporated herein by reference). Aftermetallation, the reaction mixture comprising the metallated heteroarylring is adjusted to within a temperature range of about 0° C. to aboutroom temperature and protected halo-alcohols 40 (diluted with a solventor in undiluted form) are added, preferably at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. After addition of protectedhalo-alcohols 40, the reaction mixture is stirred at a constanttemperature within the range of about room temperature and about thesolvent's boiling temperature and the reaction's progress can bemonitored by the appropriate analytical technique, preferably thin-layerchromatography or high-performance liquid chromatography. After thereaction is substantially complete, protected alcohols 42 can beisolated by workup and purification. It is to be understood thatconditions, such as the identity of protected halo-alcohol 40, the base,solvents, orders of reagent addition, times, and temperatures, can bemodified by one of skill in the art to optimize the yield andselectivity. Exemplary procedures that can be used in such atransformation are described in Shirley et al., 1995, J. Org. Chem.20:225; Chadwick et al., 1979, J. Chem. Soc., Perkin Trans. 1 2845;Rewcastle, 1993, Adv. Het. Chem. 56:208; Katritzky et al., 1993, Adv.Het. Chem. 56:155; and Kessar et al., 1997, Chem. Rev. 97:721.When Y is

protected alcohols 42 can be prepared from their correspondingcarboxylic acid derivatives (42, wherein Y is —CO₂H) as described inBelletire et al, 1988, Synthetic Commun. 18:2063 or from thecorresponding acylchlorides (42, wherein Y is —CO-halo) as described inSkinner et al., 1995, J. Am. Chem. Soc. 77:5440, both citations areincorporated herein by reference. The acylhalides can be prepared fromthe carboxylic acids by well known procedures such as those described inMarch, J., Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, pp. 437-438, hereby expressly incorporatedherein by reference. When Y is

wherein R⁷ is as defined above, protected alcohols 42 can be prepared byfirst reacting protected halo-alcohols 40 with a trialkyl phosphiteaccording to the procedure described in Kosolapoff, 1951, Org. React.6:273 followed by reacting the derived phosphonic diester with ammoniaaccording to the procedure described in Smith et al., 1957, J. Org.Chem. 22:265, incorporated herein by reference. When Y is

protected alcohols 42 can be prepared by reacting their sulphonic acidderivatives (i.e., 42, wherein Y is —SO₃H ) with ammonia as described inSianesi et al., 1971, Chem. Ber. 104:1880 and Campagna et al., 1994,Farmaco, Ed. Sci. 49:653, both of which citations are incorporatedherein by reference).

As further illustrated in Scheme 11, protected alcohols 42 can bedeprotected providing alcohols 42a. The deprotection method depends onthe identity of the alcohol-protecting group, see e.g., the procedureslisted in Greene, T. W., Protective Groups in Organic Synthesis, 3rdedition 17-237 (1999), particularly see pages 48-49, incorporated hereinby reference. One of skill in the art will readily be able to choose theappropriate deprotection procedure. When the alcohol is protected as anether function (e.g., methoxymethyl ether), the alcohol is preferablydeprotected with aqueous or alcoholic acid. Suitable deprotectionreagents include, but are not limited to, aqueous hydrochloric acid,p-toluenesulfonic acid in methanol, pyridinium-p-toluenesulfonate inethanol, Amberlyst H-15 in methanol, boric acid inethylene-glycol-monoethylether, acetic acid in a water-tetrahydrofuranmixture, aqueous hydrochloric acid is preferred. Examples of suchprocedures are described, respectively, in Bernady et al., 1979, J. Org.Chem. 44:1438; Miyashita et al., 1977, J. Org. Chem. 42:3772; Johnstonet al., 1988, Synthesis 393; Bongini et al., 1979, Synthesis 618; andHoyer et al., 1986, Synthesis 655; Gigg et al., 1967, J. Chem. Soc. C,431; and Corey et al., 1978, J. Am. Chem. Soc. 100:1942, all of whichare incorporated herein by reference.

Scheme 11 depicts the synthesis of protected lactone alcohols 46 andlactone. Compound 46 corresponds to compounds of the formulaW⁽¹⁾⁽²⁾⁻Zm-OPG and, wherein W⁽¹⁾⁽²⁾ is a lactone group selected from:

Protected lactone alcohols 46 can be prepared from compounds of theformula 46, 45, or 44 by using well-known condensation reactions andvariations of the Michael reaction. Methods for the synthesis oflactones are disclosed in Multzer in Comprehensive Organic FunctionalGroup Transformations, A. R. Katritzky, O. Meth-Cohn and C. W. Rees,Eds. Pergamon: Oxford, 1995, vol 5, pp. 161-173, incorporated herein byreference. Mono-protected diols 43, electrophilic protected alcohols 44,and aldehydes 45 are readily available ether commercially (e.g., AldrichChemical Co., Milwaukee, Wis.) or by well known synthetic procedures.

When W⁽¹⁾⁽²⁾ is a beta-lactone group of the formula:

protected lactone alcohols 46 can be prepared from aldehydes 45 andelectrophilic protected alcohols 44, respectively, by aone-pot-addition-lactonization according to the procedure of Masamune etal., 1976, J. Am. Chem. Soc. 98:7874 and Danheiser et al., 1991, J. Org.Chem. 56:1176, both of which are incorporated herein by reference. Thisone-pot-addition-lactonization methodology has been reviewed by Multzerin Comprehensive Organic Functional Group Transformations, A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Eds. Pergamon: Oxford, 1995, vol5, pp. 161, incorporated herein by reference When W⁽¹⁾⁽²⁾ is a gamma- ordelta-lactone group of the formula:

protected lactone alcohols 46 can be prepared from aldehydes 45according to well known synthetic methodology. For example, themethodology described in Masuyama et al., 2000, J. Org. Chem. 65:494;Eisch et al., 1978, J. Organo. Met. Chem. C8 160; Eaton et al., 1947, J.Org. Chem. 37:1947; Yunker et al., 1978, Tetrahedron Lett. 4651; Bhanotet al., 1977, J. Org. Chem. 42:1623; Ehlinger et al., 1980, J. Am. Chem.Soc. 102:5004; and Raunio et al., 1957, J. Org. Chem. 22:570, all ofwhich citations are incorporated herein by reference. For instance, asdescribed in Masuyama et al., 2000, J. Org. Chem. 65:494, aldehydes 45can be treated with about 1 equivalent of a strong organometallic base,preferably with a pK_(a) of about 25 or more, more preferably with apK_(a) of greater than about 35, in a suitable organic solvent to give areaction mixture. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Suitable solvents include, but are notlimited to, diethyl ether and tetrahydrofuran. The reaction-mixturetemperature is adjusted to within the range of about 0° C. to about 100°C., preferably about room temperature to about 50° C., and a halide ofthe formula:

wherein z is 1 or 2 (diluted with a solvent or in undiluted form) isadded. The reaction mixture is stirred for a period of about 2 hours toabout 48 hours, preferably about 5 to about 10 hours, during which timethe reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, protected lactone alcohols 46 can be isolated byworkup and purified if desired. When W⁽¹⁾⁽²⁾ is a ganmma- ordelta-lactone group of the formula:

protected lactone alcohols 46 can be synthesized by deprotonating thecorresponding lactone with a strong base providing the lactone enolateand reacting the enolate with electrophilic protected alcohols 44 (for adetailed discussion of enolate formation of active methylene compoundssuch as lactones, see House Modern Synthetic Reactions; W. A. Benjamin,Inc. Philippines 1972 pp. 492-570, and for a discussion of reaction oflactone enolates with electrophiles such as carbonyl compounds, seeMarch, J. Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, pp. 944-945, both of which are incorporatedherein by reference). Lactone-enolate formation can be accomplished byadding about 1 equivalent of a strong organometallic base, preferablywith a pK_(a) of about 25 or more, more preferably with a pK_(a) ofgreater than about 35, to a mixture comprising a suitable organicsolvent and the lactone. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Solvents suitable for lactone-enolateformation include, but are not limited to, diethyl ether andtetrahydrofuran. After enolate formation, the reaction-mixturetemperature is adjusted to within the range of about −78° C. to aboutroom temperature, preferably about −50° C. to about 0° C., andelectrophilic protected alcohols 44 (diluted with a solvent or inundiluted form) are added, preferably at a rate such that thereaction-mixture temperature remains within about one to two degrees ofthe initial reaction-mixture temperature. The reaction mixture isstirred for a period of about 15 minutes to about 5 hours, during whichtime the reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, protected lactone alcohols 46 can be isolated byworkup and purified if desired. When W⁽¹⁾⁽²⁾ is a lactone group group ofthe formula:

protected lactone alcohols 46 can be prepared from aldehydes 45according to the procedure described in U.S. Pat. No. 4,622,338, herebyexpressly incorporated herein by reference.

When W⁽¹⁾⁽²⁾ is a gamma- or delta-lactone group of the formula:

protected lactone alcohols 46 can be prepared according to a three stepsequence. The first step comprises base-mediated reaction ofelectrophilic protected alcohols 44 with succinic acid esters (i.e.,R⁹O₂CCH₂CH₂CO₂R⁹, wherein R⁹ is alkyl) or glutaric acid esters (i.e.,R⁹O₂CCH₂CH₂CH₂CO₂R⁹, wherein R⁹ is alkyl) providing a diesterintermediate of the formula 44i:

wherein x is 1 or 2 depending on whether the gamma or delta lactonegroup is desired. The reaction can be performed by adding about 1equivalent of a strong organometallic base, preferably with a pK_(a) ofabout 25 or more, more preferably with a pK_(a) of greater than about35, to a mixture comprising a suitable organic solvent and the succinicor glutaric acid ester. Suitable bases include, but are not limited to,alkylmetal bases such as methyllithium, n-butyllithium,tert-butyllithium, sec-butyllithium, phenyllithium, phenyl sodium, andphenyl potassium; metal amide bases such as lithium amide, sodium amide,potassium amide, lithium tetramethylpiperidide, lithiumdiisopropylamide, lithium diethylamide, lithium dicyclohexylamide,sodium hexamethyldisilazide, and lithium hexamethyldisilazide; andhydride bases such as sodium hydride and potassium hydride, preferablylithium tetramethylpiperidide. Suitable solvents include, but are notlimited to, diethyl ether and tetrahydrofuran. After enolate formation,the reaction-mixture temperature is adjusted to within the range ofabout −78° C. to about room temperature, preferably about −50° C. toabout 0° C., and electrophilic protected alcohols 44 (diluted with asolvent or in undiluted form) are added, preferably at a rate such thatthe reaction-mixture temperature remains within about one to two degreesof the initial reaction-mixture temperature. The reaction mixture isstirred for a period of about 15 minutes to about 5 hours, during whichtime the reaction's progress can be followed by using an appropriateanalytical technique, such as thin layer chromatography or highperformance liquid chromatography. When the reaction is deemedsubstantially complete, the diester intermediate be isolated by workupand purified if desired. In the second step, the intermediate diestercan be reduced, with a hydride reducing agent, to yield a diol:

The reduction can be performed according to the procedures referenced inMarch, J. Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, p. 1214, incorporated herein by reference).Suitable reducing agents include, but are not limited to, lithiumaluminum hydride, diisobutylaluminum hydride, sodium borohydride, andlithium borohydride). In the third step, the diol can be oxidativelycyclized with RuH₂(PPh₃)₄ to the product protected lactone alcohols 46according to the procedure of Yoshikawa et al., 1986, J. Org. Chem.51:2034 and Yoshikawa et al., 1983, Tetrahedron Lett. 26:2677, both ofwhich citations are incorporated herein by reference. When W⁽¹⁾⁽²⁾ is alactone group of the formula:

protected lactone alcohols 46 can be synthesized by reacting theGrignard salts of electrophilic protected alcohols 44, where E is ahalide, with 5,6-dihydro-2H-pyran-2-one, commercially available (e.g.,Aldrich Chemical Co., Milwaukee, Wis.), in the presence of catalyticamounts of a1-dimethylaminoacetyl)pyrolidine-2yl)methyl-diarylphosphine-copper(I)iodide complex as described in Tomioka et al., 1995, Tetrahedron Lett.36:4275, incorporated herein by reference.

3Scheme 12 illustrates the synthesis of ketone II. The alcohol 47 isintiallly converted to a halogen 48. See Larock, Comprehensive OrganicTransformations, VCH: New York, 1989, pp. 360-362; all referencesdisclosed therein are incorporated herein by reference. The halide 48 isthen converted to a carboxylic acid 49 with subsequent conversion to aacyl halide 50. See Larock, Comprehensive Organic Transformations, VCH:New York, 1989, pp. 850-851, 855-856, 859-860, 977, 980, and 985; allreferences discloses therein are incorporated herein by reference. Theacyl halide 50 is then coupled with the halide to afford compound II.See Rappoport, The Chemistry of the Functional Groups, Supp. D, pt. 2;Wiley: New York, 1983; House, Modern Synthetic Reactions, 2^(nd) Ed.Benjamin: New York, 1972, pp. 691-694, 734-765, which are incorporatedherein by reference.

Scheme 13 depicts the synthesis of compounds IIIa, that is, compoundsIII where a double bond is not present in the ring. In the first step,compounds 53, prepared as discussed in Schemes 1 to 6 above, can beconverted to compounds 54 by standard oxidation of the primary alcoholto an aldehyde group. Such oxidations are described in M. Hudlicky,Oxidations in Organic Chemistry, ACS Monograph 186, 1990, pp. 114-127,hereby expressly incorporated herein by reference. In the next stepGrignard reaction of 54 with 55 followed by standard OH protection gives57. Compounds 55 are commercially available (e.g., from Aldrich ChemicalCo. Milwakee, Wis.) or readily prepared by standard syntheticmethodology. For exemplary procedures for Grignard reaction see March,J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4thed., 1992, pp. 920-929, incorporated herein by reference. Similarly, inthe next step, the Grignard salt of 57 is condensed with 58 to provide59. Next 59 is is oxidized and then cyclized to 60. When p is one,exemplary cyclization procedures are found in Friedrichsen, W. inComprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, W. C.;Scriven, E. F. V. Eds.; Pergamon Press: Oxford, 1996; Vol.2, p 351, andComprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, W. C.Eds.; Pergamon Press: Oxford, 1986; Vol.3. When p is 0, cyclizationprocedures are found in Hepworth, J. D. in Comprehensive HeterocyclicChemistry II; Katritzky, A. R.; Rees, W. C.; Scriven, E. F. V. Eds.;Pergamon Press: Oxford, 1996; Vol.5, p 351 and ComprehensiveHeterocyclic Chemistry; Katritzky, A. R.; Rees, W. C. Eds.; PergamonPress: Oxford, 1986; Vol. 3, all of which citations are hereby expresslyincorporated herein by reference.

The hydroxy ketone is subjected to cyclization, as described in theabove Hepworth, J. D. in Comprehensive Heterocyclic Chemistry II;Katritzky, A. R.; Rees, W. C.; Scriven, E. F. V. Eds.; Pergamon Press:Oxford, 1996; Vol.5, p 386. For compounds III where W⁽¹⁾⁽²⁾ isHO(CH₂)_(n-)R¹R²: The hydroxy group is first deprotected as described inGreene, T. W., Protective Groups in Organic Synthesis, 3rd edition(1999). For other structures, where Y is a group such as an acid,aldehydes, etc., protection is needed (acids as esters, preferablypivaloyl, aldehydes as silyl derivatives such as TIPS, stable in bothbasic and acidic conditions). When W⁽¹⁾⁽²⁾ is a Lactone it can beintroduced as discussed in Scheme 3 above. The compounds are thencoupled to afford compound of the formula IIIa.

The reactions are performed under similar conditions for substitutedcyclic compounds. After the formation of the mono-cyclic compounds, theyare in situ reacted with electrophiles (e.g., MeI) at temperaturesbetween −40° C. to +60° C., for a reaction time of 1 hr to 5 days. Inaddition, ing double bonds can be selectively added or reduced orotherwise manipulated by well known synthetic methods to give compoundsIII having one or two selectively-placed double bonds (i.e., the doublebond(s) can be positioned in the desired location within the ring), forexample, the methods disclosed in March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 771-780,incorporated herein by reference.

4.3. Therapeutic Uses of Compounds or Compositions of the Invention

In accordance with the invention, a compound of the invention or acomposition of the invention, comprising a compound of the invention anda pharmaceutically acceptable vehicle, is administered to a patient,preferably a human, with or at risk of aging, Alzheimer's Disease,cancer, cardiovascular disease, diabetic nephropathy, diabeticretinopathy, a disorder of glucose metabolism, dyslipidemia,dyslipoproteinemia, enhancing bile production, enhancing reverse lipidtransport, hypertension, impotence, inflammation, insulin resistance,lipid elimination in bile, modulating C reactive protein, obesity,oxysterol elimination in bile, pancreatitis, Parkinson's disease, aperoxisome proliferator activated receptor-associated disorder,phospholipid elimination in bile, renal disease, septicemia, metabolicsyndrome disorders (e.g., Syndrome X), a thrombotic disorder,gastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (e.g., Crohn's Disease, ulcerative colitis), arthritis(e.g., rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g.,systemic lupus erythematosus), scleroderma, ankylosing spondylitis, goutand pseudogout, muscle pain: polymyositis/polymyalgiarheumatica/fibrositis; infection and arthritis, juvenile rheumatoidarthritis, tendonitis, bursitis and other soft tissue rheumatism. In oneembodiment, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to inhibiting theprogression of a disease or disorder, either physically, e.g.,stabilization of a discernible symptom, physiologically, e.g.,stabilization of a physical parameter, or both.

In certain embodiments, the compounds of the invention or thecompositions of the invention are administered to a patient, preferablya human, as a preventative measure against such diseases. As usedherein, “prevention” or “preventing” refers to a reduction of the riskof acquiring a given disease or disorder. In a preferred mode of theembodiment, the compositions of the present invention are administeredas a preventative measure to a patient, preferably a human having agenetic predisposition to a aging, Alzheimer's Disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,enhancing bile production, enhancing reverse lipid transport,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, septicemia, metabolic syndromedisorders (e.g., Syndrome X), a thrombotic disorder, inflammatoryprocesses and diseases like gastrointestinal disease, irritable bowelsyndrome (IBS), inflammatory bowel disease (e.g., Crohn's Disease,ulcerative colitis), arthritis (e.g., rheumatoid arthritis,osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism. Examples of such geneticpredispositions include but are not limited to the ε4 allele ofapolipoprotein E, which increases the likelihood of Alzheimer's Disease;a loss of function or null mutation in the lipoprotein lipase genecoding region or promoter (e.g., mutations in the coding regionsresulting in the substitutions D9N and N291S; for a review of geneticmutations in the lipoprotein lipase gene that increase the risk ofcardiovascular diseases, dyslipidemias and dyslipoproteinemias, seeHayden and Ma, 1992, Mol. Cell Biochem. 113:171-176); and familialcombined hyperlipidemia and familial hypercholesterolemia.

In another preferred mode of the embodiment, the compounds of theinvention or compositions of the invention are administered as apreventative measure to a patient having a non-genetic predisposition toa aging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancingreverse lipid transport, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder,inflammatory processes and diseases like gastrointestinal disease,irritable bowel syndrome (IBS), inflammatory bowel disease (e.g.,Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoidarthritis, osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism. Examples of such non-geneticpredispositions include but are not limited to cardiac bypass surgeryand percutaneous transluminal coronary angioplasty, which often lead torestenosis, an accelerated form of atherosclerosis; diabetes in women,which often leads to polycystic ovarian disease; and cardiovasculardisease, which often leads to impotence. Accordingly, the compositionsof the invention may be used for the prevention of one disease ordisorder and concurrently treating another (e.g., prevention ofpolycystic ovarian disease while treating diabetes; prevention ofimpotence while treating a cardiovascular disease).

4.4. Treatment of Cardiovascular Diseases

The present invention provides methods for the treatment or preventionof a cardiovascular disease, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, the term “cardiovascular diseases” refers todiseases of the heart and circulatory system. These diseases are oftenassociated with dyslipoproteinemias and/or dyslipidemias. Cardiovasculardiseases which the compositions of the present invention are useful forpreventing or treating include but are not limited to arteriosclerosis;atherosclerosis; stroke; ischemia; endothelium dysfunctions, inparticular those dysfunctions affecting blood vessel elasticity;peripheral vascular disease; coronary heart disease; myocardialinfarcation; cerebral infarction and restenosis.

4.5. Treatment of Dyslipidemias

The present invention provides methods for the treatment or preventionof a dyslipidemia comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle.

As used herein, the term “dyslipidemias” refers to disorders that leadto or are manifested by aberrant levels of circulating lipids. To theextent that levels of lipids in the blood are too high, the compositionsof the invention are administered to a patient to restore normal levels.Normal levels of lipids are reported in medical treatises known to thoseof skill in the art. For example, recommended blood levels of LDL, HDL,free triglycerides and others parameters relating to lipid metabolismcan be found at the web site of the American Heart Association and thatof the National Cholesterol Education Program of the National Heart,Lung and Blood Institute(http://www.americanheart.org/cholesterol/about_level.html andhttp://www.nhlbi.nih.gov/health/public/heart/chol/hbc_what.html,respectively). At the present time, the recommended level of HDLcholesterol in the blood is above 35 mg/dL; the recommended level of LDLcholesterol in the blood is below 130 mg/dL; the recommended LDL:HDLcholesterol ratio in the blood is below 5:1, ideally 3.5:1; and therecommended level of free triglycerides in the blood is less than 200mg/dL. Dyslipidemias which the compositions of the present invention areuseful for preventing or treating include but are not limited tohyperlipidemia and low blood levels of high density lipoprotein (HDL)cholesterol. In certain embodiments, the hyperlipidemia for preventionor treatment by the compounds of the present invention is familialhypercholesterolemia; familial combined hyperlipidemia; reduced ordeficient lipoprotein lipase levels or activity, including reductions ordeficiencies resulting from lipoprotein lipase mutations;hypertriglyceridemia; hypercholesterolemia; high blood levels of ureabodies (e.g. β-OH butyric acid); high blood levels of Lp(a) cholesterol;high blood levels of low density lipoprotein (LDL) cholesterol; highblood levels of very low density lipoprotein (VLDL) cholesterol and highblood levels of non-esterified fatty acids.

The present invention further provides methods for altering lipidmetabolism in a patient, e.g., reducing LDL in the blood of a patient,reducing free triglycerides in the blood of a patient, increasing theratio of HDL to LDL in the blood of a patient, and inhibiting saponifiedand/or non-saponified fatty acid synthesis, said methods comprisingadministering to the patient a compound or a composition comprising acompound of the invention in an amount effective alter lipid metabolism.

4.6. Treatment of Dyslipoproteinemias

The present invention provides methods for the treatment or preventionof a dyslipoproteinemia comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle.

As used herein, the term “dyslipoproteinemias” refers to disorders thatlead to or are manifested by aberrant levels of circulatinglipoproteins. To the extent that levels of lipoproteins in the blood aretoo high, the compositions of the invention are administered to apatient to restore normal levels. Conversely, to the extent that levelsof lipoproteins in the blood are too low, the compositions of theinvention are administered to a patient to restore normal levels. Normallevels of lipoproteins are reported in medical treatises known to thoseof skill in the art.

Dyslipoproteinemias which the compositions of the present invention areuseful for preventing or treating include but are not limited to highblood levels of LDL; high blood levels of apolipoprotein B (apo B); highblood levels of Lp(a); high blood levels of apo(a); high blood levels ofVLDL; low blood levels of HDL; reduced or deficient lipoprotein lipaselevels or activity, including reductions or deficiencies resulting fromlipoprotein lipase mutations; hypoalphalipoproteinemia; lipoproteinabnormalities associated with diabetes; lipoprotein abnormalitiesassociated with obesity; lipoprotein abnormalities associated withAlzheimer's Disease; and familial combined hyperlipidemia.

The present invention further provides methods for reducing apo C-IIlevels in the blood of a patient; reducing apo C-III levels in the bloodof a patient; elevating the levels of HDL associated proteins, includingbut not limited to apo A-I, apo A-II, apo A-IV and apo E in the blood ofa patient; elevating the levels of apo E in the blood of a patient, andpromoting clearance of triglycerides from the blood of a patient, saidmethods comprising administering to the patient a compound or acomposition comprising a compound of the invention in an amounteffective to bring about said reduction, elevation or promotion,respectively.

4.7. Treatment of Glucose Metabolism Disorders

The present invention provides methods for the treatment or preventionof a glucose metabolism disorder, comprising administering to a patienta therapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, the term “glucose metabolism disorders” refersto disorders that lead to or are manifested by aberrant glucose storageand/or utilization. To the extent that indicia of glucose metabolism(i.e., blood insulin, blood glucose) are too high, the compositions ofthe invention are administered to a patient to restore normal levels.Conversely, to the extent that indicia of glucose metabolism are toolow, the compositions of the invention are administered to a patient torestore normal levels. Normal indicia of glucose metabolism are reportedin medical treatises known to those of skill in the art.

Glucose metabolism disorders which the compositions of the presentinvention are useful for preventing or treating include but are notlimited to impaired glucose tolerance; insulin resistance; insulinresistance related breast, colon or prostate cancer; diabetes, includingbut not limited to non-insulin dependent diabetes mellitus (NIDDM),insulin dependent diabetes mellitus (IDDM), gestational diabetesmellitus (GDM), and maturity onset diabetes of the young (MODY);pancreatitis; hypertension; polycystic ovarian disease; and high levelsof blood insulin and/or glucose.

The present invention further provides methods for altering glucosemetabolism in a patient, for example to increase insulin sensitivityand/or oxygen consumption of a patient, said methods comprisingadministering to the patient a compound or a composition comprising acompound of the invention in an amount effective to alter glucosemetabolism.

4.8. Treatment of PPAR-Associated Disorders

The present invention provides methods for the treatment or preventionof a PPAR-associated disorder, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. As used herein, “treatment or prevention of PPAR associateddisorders” encompasses treatment or prevention of rheumatoid arthritis;multiple sclerosis; psoriasis; inflammatory bowel diseases; breast;colon or prostate cancer; low levels of blood HDL; low levels of blood,lymph and/or cerebrospinal fluid apo E; low blood, lymph and/orcerebrospinal fluid levels of apo A-I; high levels of blood VLDL; highlevels of blood LDL; high levels of blood triglyceride; high levels ofblood apo B; high levels of blood apo C-III and reduced ratio ofpost-heparin hepatic lipase to lipoprotein lipase activity. HDL may beelevated in lymph and/or cerebral fluid.

4.9. Treatment of Renal Diseases

The present invention provides methods for the treatment or preventionof a renal disease, comprising administering to a patient atherapeutically effective amount of a compound or a compositioncomprising a compound of the invention and a pharmaceutically acceptablevehicle. Renal diseases that can be treated by the compounds of thepresent invention include glomerular diseases (including but not limitedto acute and chronic glomerulonephritis, rapidly progressiveglomerulonephritis, nephrotic syndrome, focal proliferativeglomerulonephritis, glomerular lesions associated with systemic disease,such as systemic lupus erythematosus, Goodpasture's syndrome, multiplemyeloma, diabetes, neoplasia, sickle cell disease, and chronicinflammatory diseases), tubular diseases (including but not limited toacute tubular necrosis and acute renal failure, polycystic renaldiseasemedullary sponge kidney, medullary cystic disease, nephrogenicdiabetes, and renal tubular acidosis), tubulointerstitial diseases(including but not limited to pyelonephritis, drug and toxin inducedtubulointerstitial nephritis, hypercalcemic nephropathy, and hypokalemicnephropathy) acute and rapidly progressive renal failure, chronic renalfailure, nephrolithiasis, or tumors (including but not limited to renalcell carcinoma and nephroblastoma). In a most preferred embodiment,renal diseases that are treated by the compounds of the presentinvention are vascular diseases, including but not limited tohypertension, nephrosclerosis, microangiopathic hemolytic anemia,atheroembolic renal disease, diffuse cortical necrosis, and renalinfarcts.

4.10. Treatment of Cancer

The present invention provides methods for the treatment or preventionof cancer, comprising administering to a patient a therapeuticallyeffective amount of a compound or a composition comprising a compound ofthe invention and a pharmaceutically acceptable vehicle. Types of cancerthat can be treated using a Compound of the Invention include, but arenot limited to, those listed in Table 2. TABLE 2 Solid tumors, includingbut not limited to fibrosarcoma myxosarcoma liposarcoma chondrosarcomaosteogenic sarcoma chordoma angiosarcoma endotheliosarcomalymphangiosarcoma lymphangioendotheliosarcoma synovioma mesotheliomaEwing's tumor leiomyosarcoma rhabdomyosarcoma colon cancer colorectalcancer kidney cancer pancreatic cancer bone cancer breast cancer ovariancancer prostate cancer esophogeal cancer stomach cancer oral cancernasal cancer throat cancer squamous cell carcinoma basal cell carcinomaadenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillarycarcinoma papillary adenocarcinomas cystadenocarcinoma medullarycarcinoma bronchogenic carcinoma renal cell carcinoma hepatoma bile ductcarcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumorcervical cancer uterine cancer testicular cancer small cell lungcarcinoma bladder carcinoma lung cancer epithelial carcinoma gliomaglioblastoma multiforme astrocytoma medulloblastoma craniopharyngiomaependymoma pinealoma hemangioblastoma acoustic neuroma oligodendrogliomameningioma skin cancer melanoma neuroblastoma retinoblastoma Blood-bornecancers, including but not limited to: acute lymphoblastic B-cellleukemia acute lymphoblastic T-cell leukemia acute myeloblastic leukemia“AML” acute promyelocytic leukemia “APL” acute monoblastic leukemiaacute erythroleukemic leukemia acute megakaryoblastic leukemia acutemyelomonocytic leukemia acute nonlymphocyctic leukemia acuteundifferentiated leukemia chronic myelocytic leukemia “CML” chroniclymphocytic leukemia “CLL” hairy cell leukemia multiple myeloma Acuteand chronic leukemias Lymphoblastic myelogenous lymphocytic myelocyticleukemias Lymphomas: Hodgkin's disease non-Hodgkin's Lymphoma Multiplemyeloma Waldenstrom's macroglobulinemia Heavy chain disease Polycythemiavera

Cancer, including, but not limited to, a tumor, metastasis, or anydisease or disorder characterized by uncontrolled cell growth, can betreated or prevented by administration of a Compound of the Invention.

4.11. Treatment of Other Diseases

The present invention provides methods for the treatment or preventionof aging, Alzheimer's Disease, cancer, cardiovascular disease, diabeticnephropathy, diabetic retinopathy, a disorder of glucose metabolism,dyslipidemia, dyslipoproteinemia, enhancing bile production, enhancingreverse lipid transport, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder,inflammatory processes and diseases like gastrointestinal disease,irritable bowel syndrome (IBS), inflammatory bowel disease (e.g.,Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoidarthritis, osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism, comprising administering to apatient a therapeutically effective amount of a compound or acomposition comprising a compound of the invention and apharmaceutically acceptable vehicle.

As used herein, “treatment or prevention of Alzheimer's Disease”encompasses treatment or prevention of lipoprotein abnormalitiesassociated with Alzheimer's Disease.

As used herein, “treatment or prevention of Syndrome X or MetabolicSyndrome” encompasses treatment or prevention of a symptom thereof,including but not limited to impaired glucose tolerance, hypertensionand dyslipidemia/dyslipoproteinemia.

As used herein, “treatment or prevention of septicemia” encompassestreatment or prevention of septic shock.

As used herein, “treatment or prevention of thrombotic disorders”encompasses treatment or prevention of high blood levels of fibrinogenand promotion of fibrinolysis. In addition to treating or preventingobesity, the compositions of the invention can be administered to anindividual to promote weight reduction of the individual.

As used herein, “treatment or prevention of diabetic nephropathy”encompasses treating or preventing kidney disease that develops as aresult of diabetes mellitus (DM). Diabetes mellitus is a disorder inwhich the body is unable to metabolize carbohydrates (e.g., foodstarches, sugars, cellulose) properly. The disease is characterized byexcessive amounts of sugar in the blood (hyperglycemia) and urine;inadequate production and/or utilization of insulin; and by thirst,hunger, and loss of weight. Thus, the compounds of the invention canalso be used to treat or prevent diabetes mellitus.

As used herein, “treatment or prevention of diabetic retinopathy”encompasses treating or preventing complications of diabetes that leadto or cause blindness. Diabetic retinopathy occurs when diabetes damagesthe tiny blood vessels inside the retina, the light-sensitive tissue atthe back of the eye.

As used herein, “treatment or prevention of impotence” includes treatingor preventing erectile dysfunction, which encompasses the repeatedinability to get or keep an erection firm enough for sexual intercourse.The word “impotence” may also be used to describe other problems thatinterfere with sexual intercourse and reproduction, such as lack ofsexual desire and problems with ejaculation or orgasm. The term“treatment or prevention of impotence includes, but is not limited toimpotence that results as a result of damage to nerves, arteries, smoothmuscles, and fibrous tissues, or as a result of disease, such as, butnot limited to, diabetes, kidney disease, chronic alcoholism, multiplesclerosis, atherosclerosis, vascular disease, and neurologic disease.

As used herein, “treatment or prevention of hypertension” encompassestreating or preventing blood flow through the vessels at a greater thannormal force, which strains the heart; harms the arteries; and increasesthe risk of heart attack, stroke, and kidney problems. The termhypertension includes, but is not limited to, cardiovascular disease,essential hypertension, hyperpiesia, hyperpiesis, malignanthypertension, secondary hypertension, or white-coat hypertension.

As used herein, “treatment or prevention of inflammation” encompassestreating or preventing inflammation diseases including, but not limitedto, chronic inflammatory disorders of the joints including arthritis,e.g., rheumatoid arthritis and osteoarthritis; respiratory distresssyndrome, inflammatory bowel diseases such as ileitis, ulcerativecolitis and Crohn's disease; and inflammatory lung disorders such asasthma and chronic obstructive airway disease, inflammatory disorders ofthe eye such as corneal dystrophy, trachoma, onchocerciasis, uveitis,sympathetic ophthalmitis, and endophthalmitis; inflammatory disorders ofthe gum, e.g., periodontitis and gingivitis; tuberculosis; leprosy;inflammatory diseases of the kidney including glomerulonephritis andnephrosis; inflammatory disorders of the skin including acne,sclerodermatitis, psoriasis, eczema, photoaging and wrinkles;inflammatory diseases of the central nervous system, includingAIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer'sdisease, encephalomyelitis and viral or autoimmune encephalitis;autoimmune diseases including immune-complex vasculitis, systemic lupusand erythematodes; systemic lupus erythematosus (SLE); and inflammatorydiseases of the heart such as cardiomyopathy.

4.12. Combination Therapy

In certain embodiments of the present invention, the compounds andcompositions of the invention can be used in combination therapy with atleast one other therapeutic agent. The compound of the invention and thetherapeutic agent can act additively or, more preferably,synergistically. In a preferred embodiment, a compound or a compositioncomprising a compound of the invention is administered concurrently withthe administration of another therapeutic agent, which can be part ofthe same composition as the compound of the invention or a differentcomposition. In another embodiment, a compound or a compositioncomprising a compound of the invention is administered prior orsubsequent to administration of another therapeutic agent. As many ofthe disorders for which the compounds and compositions of the inventionare useful in treating are chronic disorders, in one embodimentcombination therapy involves alternating between administering acompound or a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of each drug or therapeutic agent can be, e.g., onemonth, three months, six months, or a year. In certain embodiments, whena composition of the invention is administered concurrently with anothertherapeutic agent that potentially produces adverse side effectsincluding but not limited to toxicity, the therapeutic agent canadvantageously be administered at a dose that falls below the thresholdat which the adverse side is elicited.

The present compositions can be administered together with a statin.Statins for use in combination with the compounds and compositions ofthe invention include but are not limited to atorvastatin, pravastatin,fluvastatin, lovastatin, simvastatin, and cerivastatin.

The present compositions can also be administered together with a PPARagonist, for example a thiazolidinedione or a fibrate.Thiazolidinediones for use in combination with the compounds andcompositions of the invention include but are not limited to 5 ((4 (2(methyl 2 pyridinylamino)ethoxy)phenyl)methyl)2,4 thiazolidinedione,troglitazone, pioglitazone, ciglitazone, WAY 120,744, englitazone, AD5075, darglitazone, and rosiglitazone. Fibrates for use in combinationwith the compounds and compositions of the invention include but are notlimited to gemfibrozil, fenofibrate, clofibrate, or ciprofibrate. Asmentioned previously, a therapeutically effective amount of a fibrate orthiazolidinedione often has toxic side effects. Accordingly, in apreferred embodiment of the present invention, when a composition of theinvention is administered in combination with a PPAR agonist, the dosageof the PPAR agonist is below that which is accompanied by toxic sideeffects.

The present compositions can also be administered together with a bileacid binding resin. Bile acid binding resins for use in combination withthe compounds and compositions of the invention include but are notlimited to cholestyramine and colestipol hydrochloride. The presentcompositions can also be administered together with niacin or nicotinicacid. The present compositions can also be administered together with aRXR agonist. RXR agonists for use in combination with the compounds ofthe invention include but are not limited to LG 100268, LGD 1069, 9-cisretinoic acid, 2 (1 (3,5,5,8,8 pentamethyl 5,6,7,8 tetrahydro 2naphthyl)cyclopropyl)pyridine 5 carboxylic acid, or 4 ((3,5,5,8,8pentamethyl 5,6,7,8 tetrahydro 2 naphthyl)2 carbonyl)benzoic acid. Thepresent compositions can also be administered together with ananti-obesity drug. Anti-obesity drugs for use in combination with thecompounds of the invention include but are not limited to β-adrenergicreceptor agonists, preferably β-3 receptor agonists, fenfluramine,dexfenfluramine, sibutramine, bupropion, fluoxetine, and phentermine.The present compositions can also be administered together with ahormone. Hormones for use in combination with the compounds of theinvention include but are not limited to thyroid hormone, estrogen andinsulin. Preferred insulins include but are not limited to injectableinsulin, transdermal insulin, inhaled insulin, or any combinationthereof. As an alternative to insulin, an insulin derivative,secretagogue, sensitizer or mimetic may be used. Insulin secretagoguesfor use in combination with the compounds of the invention include butare not limited to forskolin, dibutryl cAMP or isobutylmethylxanthine(IBMX).

The present compositions can also be administered together with aphosphodiesterase type 5 (“PDE5”) inhibitor to treat or preventdisorders, such as but not limited to, impotence. In a particular,embodiment the combination is a synergistic combination of a compositionof the invention and a PDE5 inhibitor.

The present compositions can also be administered together with atyrophostine or an analog thereof. Tyrophostines for use in combinationwith the compounds of the invention include but are not limited totryophostine 51.

The present compositions can also be administered together withsulfonylurea-based drugs. Sulfonylurea-based drugs for use incombination with the compounds of the invention include, but are notlimited to, glisoxepid, glyburide, acetohexamide, chlorpropamide,glibomuride, tolbutamide, tolazamide, glipizide, gliclazide, gliquidone,glyhexamide, phenbutamide, and tolcyclamide. The present compositionscan also be administered together with a biguanide. Biguanides for usein combination with the compounds of the invention include but are notlimited to metformin, phenformin and buformin.

The present compositions can also be administered together with anα-glucosidase inhibitor. α-glucosidase inhibitors for use in combinationwith the compounds of the invention include but are not limited toacarbose and miglitol.

The present compositions can also be administered together with an apoA-I agonist. In one embodiment, the apo A-I agonist is the Milano formof apo A-I (apo A-IM). In a preferred mode of the embodiment, the apoA-IM for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,721,114 toAbrahamsen. In a more preferred embodiment, the apo A-I agonist is apeptide agonist. In a preferred mode of the embodiment, the apo A-Ipeptide agonist for administration in conjunction with the compounds ofthe invention is a peptide of U.S. Pat. No. 6,004,925 or U.S. Pat. No.6,037,323 to Dasseux.

The present compositions can also be administered together withapolipoprotein E (apo E). In a preferred mode of the embodiment, theapoE for administration in conjunction with the compounds of theinvention is produced by the method of U.S. Pat. No. 5,834,596 toAgeland.

In yet other embodiments, the present compositions can be administeredtogether with an HDL-raising drug; an HDL enhancer; or a regulator ofthe apolipoprotein A-I, apolipoprotein A-IV and/or apolipoprotein genes.In one embodiment, the other therapeutic agent can be an antiemeticagent. Suitable antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,thioproperazine and tropisetron.

In another embodiment, the other therapeutic agent can be anhematopoietic colony stimulating factor. Suitable hematopoietic colonystimulating factors include, but are not limited to, filgrastim,sargramostim, molgramostim and erythropoietin alfa. In still anotherembodiment, the other therapeutic agent can be an opioid or non-opioidanalgesic agent. Suitable opioid analgesic agents include, but are notlimited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone,oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine,meperidine, lopermide, anileridine, ethoheptazine, piminidine,betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil,remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine,cyclazocine, methadone, isomethadone and propoxyphene. Suitablenon-opioid analgesic agents include, but are not limited to, aspirin,celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen,flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac,meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam andsulindac.

4.13. Combination Therapy of Cardiovascular Diseases

The present compositions can be administered together with a knowncardiovascular drug. Cardiovascular drugs for use in combination withthe compounds of the invention to prevent or treat cardiovasculardiseases include but are not limited to peripheral antiadrenergic drugs,centrally acting antihypertensive drugs (e.g., methyldopa, methyldopaHCl), antihypertensive direct vasodilators (e.g., diazoxide, hydralazineHCl), drugs affecting renin-angiotensin system, peripheral vasodilators,phentolamine, antianginal drugs, cardiac glycosides, inodilators (e.g.,aminone, milrinone, enoximone, fenoximone, imazodan, sulmazole),antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, andrezulin.

4.14. Combination Therapy of Cancer

The present invention includes methods for treating cancer, comprisingadministering to an animal in need thereof an effective amount of aCompound of the Invention and another therapeutic agent that is ananti-cancer agent. Suitable anticancer agents include, but are notlimited to, those listed in Table 3. TABLE 3 Alkylating agents Nitrogenmustards: Cyclophosphamide Ifosfamide trofosfamide Chlorambucil TreosNitrosoureas: carbustine (BCNU) Lomustine (CCNU) AlkylsulphonatesBusulfan Treosulfan Triazenes: Dacarbazine Platinum containingcompounds: Cisplatin carboplatin Plant Alkaloids Vinca alkaloids:Vicristine Vinblastine Vindesine Vinorelbine Taxoids: paclitaxelDocetaxol DNA Topoisomerase Inhibitors Epipodophyllins: EtoposideTeniposide Topotecan 9-aminocamptothecin camptothecin crisnatolmitomycins: Mitomycin C Anti-metabolites Anti-folates: DHFR inhibitors:METHOTREXATE Trimetrexate IMP dehydrogenase Inhibitors: Mycophenolicacid Tiazofurin Ribavirin EICAR Ribonuclotide reductase Inhibitors:Hydroxyurea deferoxamine Pyrimidine analogs: Uracil analogs5-Fluorouracil Floxuridine Doxifluridine Ratitrexed Cytosine analogscytarabine (ara C) Cytosine arabinoside fludarabine Purine analogs:mercaptopurine Thioguanine Hormonal therapies: Receptor antagonists:Anti-estrogen Tamoxifen Raloxifene megestrol goscrclin Leuprolideacetate LHRH agonists: flutamide bicalutamide Retinoids/Deltoids VitaminD3 analogs: EB 1089 CB 1093 KH 1060 Photodynamic therapies: vertoporfin(BPD-MA) Phthalocyanine photosensitizer Pc4 Demethoxy-hypocrellin A(2BA-2-DMHA) Cytokines: Interferon-α Interferon-γ Tumor necrosis factorOthers: Isoprenylation inhibitors: Lovastatin Dopaminergic neurotoxins:1-methyl-4-phenylpyridinium ion Cell cycle inhibitors: staurosporineActinomycines: Actinomycin D Dactinomycin Bleomycins: bleomycin A2Bleomycin B2 Peplomycin Anthracyclines: daunorubicin Doxorubicin(adriamycin) Idarubicin Epirubicin Pirarubicin Zorubicin MitoxantroneMDR inhibitors verapamil Ca²⁺ ATPase inhibitors: thapsigargin

In a specific embodiment, a composition of the invention furthercomprises one or more chemotherapeutic agents and/or is administeredconcurrently with radiation therapy. In another specific embodiment,chemotherapy or radiation therapy is administered prior or subsequent toadministration of a present composition, preferably at least an hour,five hours, 12 hours, a day, a week, a month, more preferably severalmonths (e.g., up to three months), subsequent to administration of acomposition of the invention.

In other embodiments, the invention provides methods for treating orpreventing cancer, comprising administering to an animal in need thereofan effective amount of a Compound of the Invention and achemotherapeutic agent. In one embodiment the chemotherapeutic agent isthat with which treatment of the cancer has not been found to berefractory. In another embodiment, the chemotherapeutic agent is thatwith which the treatment of cancer has been found to be refractory. TheCompounds of the Invention can be administered to an animal that hasalso undergone surgery as treatment for the cancer.

In one embodiment, the additional method of treatment is radiationtherapy. In a specific embodiment, the Compound of the Invention isadministered concurrently with the chemotherapeutic agent or withradiation therapy. In another specific embodiment, the chemotherapeuticagent or radiation therapy is administered prior or subsequent toadministration of a Compound of the Invention, preferably at least anhour, five hours, 12 hours, a day, a week, a month, more preferablyseveral months (e.g., up to three months), prior or subsequent toadministration of a Compound of the Invention.

A chemotherapeutic agent can be administered over a series of sessions,any one or a combination of the chemotherapeutic agents listed in Table3 can be administered. With respect to radiation, any radiation therapyprotocol can be used depending upon the type of cancer to be treated.For example, but not by way of limitation, x-ray radiation can beadministered; in particular, high-energy megavoltage (radiation ofgreater that 1 MeV energy) can be used for deep tumors, and electronbeam and orthovoltage x-ray radiation can be used for skin cancers.Gamma-ray emitting radioisotopes, such as radioactive isotopes ofradium, cobalt and other elements, can also be administered.Additionally, the invention provides methods of treatment of cancer witha Compound of the Invention as an alternative to chemotherapy orradiation therapy where the chemotherapy or the radiation therapy hasproven or can prove too toxic, e.g., results in unacceptable orunbearable side effects, for the subject being treated. The animal beingtreated can, optionally, be treated with another cancer treatment suchas surgery, radiation therapy or chemotherapy, depending on whichtreatment is found to be acceptable or bearable.

The Compounds of the Invention can also be used in an in vitro or exvivo fashion, such as for the treatment of certain cancers, including,but not limited to leukemias and lymphomas, such treatment involvingautologous stem cell transplants. This can involve a multi-step processin which the animal's autologous hematopoietic stem cells are harvestedand purged of all cancer cells, the patient's remaining bone-marrow cellpopulation is then eradicated via the administration of a high dose of aCompound of the Invention with or without accompanying high doseradiation therapy, and the stem cell graft is infused back into theanimal. Supportive care is then provided while bone marrow function isrestored and the animal recovers.

4.15. Surgical Uses

Cardiovascular diseases such as atherosclerosis often require surgicalprocedures such as angioplasty. Angioplasty is often accompanied by theplacement of a reinforcing a metallic tube shaped structure known as a“stent” into a damaged coronary artery. For more serious conditions,open heart surgery such as coronary bypass surgery may be required.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds and compositions of the inventionmay be used as coatings on surgical devices (e.g., catheters) andimplants (e.g., stents) to reduce the risk of restenosis and thrombosisassociated with invasive procedures used in the treatment ofcardiovascular diseases.

4.16. Veterinary and Livestock Uses

A composition of the invention can be administered to a non-human animalfor a veterinary use for treating or preventing a disease or disorderdisclosed herein. In a specific embodiment, the non-human animal is ahousehold pet. In another specific embodiment, the non-human animal is alivestock animal. In a preferred embodiment, the non-human animal is amammal, most preferably a cow, horse, sheep, pig, cat, dog, mouse, rat,rabbit, or guinea pig. In another preferred embodiment, the non-humananimal is a fowl species, most preferably a chicken, turkey, duck,goose, or quail.

In addition to veterinary uses, the compounds and compositions of theinvention can be used to reduce the fat content of livestock to produceleaner meats. Alternatively, the compounds and compositions of theinvention can be used to reduce the cholesterol content of eggs byadministering the compounds to a chicken, quail, or duck hen. Fornon-human animal uses, the compounds and compositions of the inventioncan be administered via the animals' feed or orally as a drenchcomposition.

4.17. Therapeutic/Prophylactic Administration and Compositions

Due to the activity of the compounds and compositions of the invention,they are useful in veterinary and human medicine. As described above,the compounds and compositions of the invention are useful for thetreatment or prevention of aging, Alzheimer's Disease, cancer,cardiovascular disease, diabetic nephropathy, diabetic retinopathy, adisorder of glucose metabolism, dyslipidemia, dyslipoproteinemia,hypertension, impotence, inflammation, insulin resistance, lipidelimination in bile, modulating C reactive protein, obesity, oxysterolelimination in bile, pancreatitis, Parkinson's disease, a peroxisomeproliferator activated receptor-associated disorder, phospholipidelimination in bile, renal disease, septicemia, metabolic syndromedisorders (e.g., Syndrome X), a thrombotic disorder, enhancing bileproduction, enhancing reverse lipid transport, inflammatory processesand diseases like gastrointestinal disease, irritable bowel syndrome(IBS), inflammatory bowel disease (e.g., Crohn's Disease, ulcerativecolitis), arthritis (e.g., rheumatoid arthritis, osteoarthritis),autoimmune disease (e.g., systemic lupus erythematosus), scleroderma,ankylosing spondylitis, gout and pseudogout, muscle pain:polymyositis/polymyalgia rheumatica/fibrositis; infection and arthritis,juvenile rheumatoid arthritis, tendonitis, bursitis and other softtissue rheumatism.

The invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acompound or a composition comprising a compound of the invention. Thepatient is an animal, including, but not limited, to an animal such acow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat,rabbit, guinea pig, etc., and is more preferably a mammal, and mostpreferably a human.

The compounds and compositions of the invention, are preferablyadministered orally. The compounds and compositions of the invention mayalso be administered by any other convenient route, for example, byintravenous infusion or bolus injection, by absorption throughepithelial or mucocutaneous linings (e.g., oral mucosa, rectal andintestinal mucosa, etc.) and may be administered together with anotherbiologically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, capsules, etc., and can be used toadminister a compound of the invention. In certain embodiments, morethan one compound of the invention is administered to a patient. Methodsof administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The preferred mode of administration is leftto the discretion of the practitioner, and will depend in-part upon thesite of the medical condition. In most instances, administration willresult in the release of the compounds of the invention into thebloodstream.

In specific embodiments, it may be desirable to administer one or morecompounds of the invention locally to the area in need of treatment.This may be achieved, for example, and not by way of limitation, bylocal infusion during surgery, topical application, e.g., in conjunctionwith a wound dressing after surgery, by injection, by means of acatheter, by means of a suppository, or by means of an implant, saidimplant being of a porous, non-porous, or gelatinous material, includingmembranes, such as sialastic membranes, or fibers. In one embodiment,administration can be by direct injection at the site (or former site)of an atherosclerotic plaque tissue.

In certain embodiments, for example, for the treatment of Alzheimer'sDisease, it may be desirable to introduce one or more compounds of theinvention into the central nervous system by any suitable route,including intraventricular, intrathecal and epidural injection.Intraventricular injection may be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the compounds of the invention can be formulated asa suppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the compounds and compositions of the inventioncan be delivered in a vesicle, in particular a liposome (see Langer,1990, Science 249:1527 1533; Treat et al., in Liposomes in the Therapyof Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),Liss, New York, pp. 353 365 (1989); Lopez Berestein, ibid., pp. 317 327;see generally ibid.).

In yet another embodiment, the compounds and compositions of theinvention can be delivered in a controlled release system. In oneembodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRCCrit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974);Controlled Drug Bioavailability, Drug Product Design and Performance,Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983,J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al.,1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howardet al., 1989, J. Neurosurg. 71:105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target areato be treated, e.g., the liver, thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, in Medical Applications of ControlledRelease, supra, vol. 2, pp. 115 138 (1984)). Other controlled-releasesystems discussed in the review by Langer, 1990, Science 249:1527 1533)may be used.

The present compositions will contain a therapeutically effective amountof a compound of the invention, optionally more than one compound of theinvention, preferably in purified form, together with a suitable amountof a pharmaceutically acceptable vehicle so as to provide the form forproper administration to the patient.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “vehicle” refers to a diluent, adjuvant, excipient, or carrier withwhich a compound of the invention is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds and compositions of theinvention and pharmaceutically acceptable vehicles are preferablysterile. Water is a preferred vehicle when the compound of the inventionis administered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in “Remington's PharmaceuticalSciences” by E. W. Martin.

In a preferred embodiment, the compounds and compositions of theinvention are formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous administration tohuman beings. Typically, compounds and compositions of the invention forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the compositions may also include asolubilizing agent. Compositions for intravenous administration mayoptionally include a local anesthetic such as lignocaine to ease pain atthe site of the injection. Generally, the ingredients are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the compound of the invention is to beadministered by intravenous infusion, it can be dispensed, for example,with an infusion bottle containing sterile pharmaceutical grade water orsaline. Where the compound of the invention is administered byinjection, an ampoule of sterile water for injection or saline can beprovided so that the ingredients may be mixed prior to administration.

Compounds and compositions of the invention for oral delivery may be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs. Compounds andcompositions of the invention for oral delivery can also be formulatedin foods and food mixes. Orally administered compositions may containone or more optionally agents, for example, sweetening agents such asfructose, aspartame or saccharin; flavoring agents such as peppermint,oil of wintergreen, or cherry; coloring agents; and preserving agents,to provide a pharmaceutically palatable preparation. Moreover, where intablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andcompositions of the invention. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to 2000 milligrams ofa compound of the invention per kilogram body weight. In specificpreferred embodiments of the invention, the oral dose is 0.01 milligramto 1000 milligrams per kilogram body weight, more preferably 0.1milligram to 100 milligrams per kilogram body weight, more preferably0.5 milligram to 25 milligrams per kilogram body weight, and yet morepreferably 1 milligram to 10 milligrams per kilogram body weight. In amost preferred embodiment, the oral dose is 5 milligrams of a compoundof the invention per kilogram body weight. The dosage amounts describedherein refer to total amounts administered; that is, if more than onecompound of the invention is administered, the preferred dosagescorrespond to the total amount of the compounds of the inventionadministered. Oral compositions preferably contain 10% to 95% activeingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are 0.01milligram to 1000 milligrams per kilogram body weight, 0.1 milligram to350 milligrams per kilogram body weight, and 1 milligram to 100milligrams per kilogram body weight. Suitable dosage ranges forintranasal administration are generally about 0.01 pg/kg body weight to1 mg/kg body weight. Suppositories generally contain 0.01 milligram to50 milligrams of a compound of the invention per kilogram body weightand comprise active ingredient in the range of 0.5% to 10% by weight.Recommended dosages for intradermal, intramuscular, intraperitoneal,subcutaneous, epidural, sublingual, intracerebral, intravaginal,transdermal administration or administration by inhalation are in therange of 0.001 milligram to 200 milligrams per kilogram of body weight.Suitable doses of the compounds of the invention for topicaladministration are in the range of 0.001 milligram to 1 milligram,depending on the area to which the compound is administered. Effectivedoses may be extrapolated from dose-response curves derived from invitro or animal model test systems. Such animal models and systems arewell known in the art.

The invention also provides pharmaceutical packs or kits comprising oneor more containers filled with one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In a certain embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises acompound of the invention and another lipid-mediating compound,including but not limited to a statin, a thiazolidinedione, or afibrate.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred for lowering fatty acidsynthesis. The compounds and compositions of the invention may also bedemonstrated to be effective and safe using animal model systems.

Other methods will be known to the skilled artisan and are within thescope of the invention.

The following examples are provided by way of illustration and notlimitation.

5. EXAMPLES 5.1. Keto-substituted α-Cycloalkyldicarboxylic Acids

The cycloalkyl substituted keto-derivatives II are prepared as shown inScheme 14 by methods already described in Dasseux, J.-L. H. et al.Ketone compounds and compositions for cholesterol management and relateduses. U.S. patent application publication 20030078239, Oct. 11, 2001.The key step in the syntheses of most of the compounds of the inventionis the alkylation of the formaldehyde synthon: Tosylmethyl Isocyanide(TosMIC) (Possel, O. et al. Tetrahedron Lett., 1977, 17, 4229-4232;Kurosawa, K. et al. Tetrahedron Lett., 1982, 23, 5335-5338; Yadav, J. S.et al. Tetrahedron Lett., 1990, 31, 6217-6218; van Leusen, D. et al.Synthetic Uses of Tosylmethyl Isocyanide (TosMIC). In Organic Reactions,Vol. 57; Overman, L. E., Editor-in-Chief; John Wiley and Sons, Inc.: NewYork, 2001; pp 417-666) with a properly functionalized halo-ester, whichis available commercially (e.g., Aldrich Chemical Co., Milwaukee, Wis.)or can be prepared by well-known methods such as halogenation orsulfonation of butanediol.

In a typical procedure, a halo-ester is prepared via alkylation ofcommercially available or known esters of type 101 with a dihaloalkaneof type 102 of proper length as described in Scheme 15. Cycloakylcarboxylic esters of type 101 prepared for this invention are used forthe preparation of haloesters described in Table 1. Ethyl, butyl andt-butyl ester analogues of 101 could be used as starting material. As anexample, ethyl cyclopropylcarboxylate, which is known to self-condensateon treatment with various bases, as described in Pinnick, H. W. et al.J. Org. Chem., 1980, 45, 4505-4507, cannot be used for this reaction,and the corresponding t-butyl analogue is used instead, which isprepared as described in the literature (Haener, R. et al. Helv. Chim.Acta, 1986, 69, 1655-1665). In a typical procedure, bromo-esters 103a-gare prepared via treatment of 101 with LDA and a large excess of adibromoalkane (102, X=Br) or bromo-chloroalkane (102, X=Cl) in THF atlow temperatures. The crude product 104 is separated from excess of 102via fractional distillation. If iododerivatives are needed due to thelack of reactivity of the chloro-ester derivatives (104a-c), the latterare converted to the corresponding iodides (105a-c) by methods known inthe literature prior to their reaction with TosMIC. In the case of thebromo-esters (103a-g) treatment with a catalytic amount of Bu₄NIsuffices to form the corresponding iodo compounds in situ.

TABLE 1 Synthesis of halo-esters 103a-g, 104a-c and 105a-c. Compound m RR1 R2 X Yield (%) 103a 4 Et Me Me Br ^(a) 103b 4 tBu cyclo-Propyl Br34^(b) 103c 4 Bu cyclo-Pentyl Br 49 103d 4 Et CO₂Et Me Br ^(c) 103e 5 EtMe Me Br ^(a) 103f 5 Bu cyclo-Pentyl Br 61^(b) 103g 7 Et Me Me Br 45104a 4 tBu cyclo-Propyl Cl 52 104b 4 Et cyclo-Butyl Cl 86 104c 5 tBucyclo-Propyl Cl 73 105a 4 tBu cyclo-Propyl I 94^(b) 105b 4 Etcyclo-Butyl I 99 105c 5 tBu cyclo-Propyl I 99^(a)See: Ackerley, N. et al. J. Med. Chem., 1995, 38, 1608-1628.^(b)Purity >90%.^(c)See: Astles, P. C. et al. J. Med. Chem., 1996, 39, 1423-1432.

Symmetrical ketones are prepared by Method A (e.g. TosMIC, NaH, 3, Bu₄NIin DMSO) as described in Scheme 16. The intermediate dialkylated TosMICderivatives is treated with conc HCl in CH₂Cl₂ to provide keto-diesters106d,g-h,j,m-n in moderate to good yield as shown in Scheme 15 and Table2. For the preparation of keto-diacids 106c,e-f,k-l Method B is applied(e.g., KOtBu, 105 in N,N-dimethylacetamide at temperatures between −10°C. to 35° C., preferably room temperature), which is similar to the onedescribed by Haener, R. et al. Helv. Chim. Acta, 1986, 69, 1655-1665 andproducts are obtained as described in Table 2.

For the preparation of asymmetrical ketones 106c,e,k a set ofmono-alkylated TosMIC derivatives (108a,b) are used as startingmaterials that are prepared as described in Scheme 17. As suchintermediates could only be produced in low yield via Method A the moreselective conditions (K₂CO₃, DMAc) are applied, providing 108a,b in goodyield (Table 3). Subsequent treatment of 108a,b as reported for Method Aor B afforded the asymmetrical ketones 106c,e,k (Table 2). The targetketo-diacids (107) were prepared from the corresponding ester analogues(106) by saponification of the linear alkane esters (Et, Bu), treatmentof the t-butyl esters with HCO₂H or a combination of the two (Schemes 3and 4). Preparations are similar for compounds with other terminalgroups than acids, as described in Dasseux, J.-L. H. et al. Ketonecompounds and compositions for cholesterol management and related uses.U.S. patent application 20030078239, Oct. 11, 2001

TABLE 2 Syntheses of keto-esters (106) and corresponding keto-acids(107) using TosMIC chemistry. Compound 107 Elemental Analysis Compound 6106→ 107 Found (Calculated) Yield Meth- Yield mp 106 m n R R1 R2 R3 R4R5 Method⁶ (%) od⁶ (%) C H (° C.) c 4 4 CO₂Et CO₂tBu Me Me cyclo-PropylC 43^(b) F 80^(b) 65.06 (65.36) 9.02 (9.03) 49-52 d 4 4 CO₂tBu CO₂tBucyclo-Propyl cyclo-Propyl A 49 E 99 65.40 (65.78) 8.37 (8.44) 132-134 e4 4 CO₂Et CO₂Et Me Me cyclo-Butyl C 75^(b) D 76

53-55 f 4 4 CO₂Et CO₂Et cyclo-Butyl cyclo-Butyl B 82 D 56 67.19 (67.43)8.97 (8.93) 69-70 g 4 4 CO₂Bu CO₂Bu cyclo-Pentyl cyclo-Pentyl A 56 D94^(b) 68.78 (68.82) 9.47 (9.35) 104-106 h 4 4 CO₂Et CO₂Et Me CO₂Et MeCO₂Et A 71 ^(c) 81 — — — k 5 5 CO₂Et CO₂tBu Me Me cyclo-Propyl C 57^(b)F 84 66.86 (67.03) 9.50 (9.47) 65-66 I 5 5 CO₂tBu CO₂tBu cyclo-Propylcyclo-Propyl B 46^(b) E 99 67.20 (67.43) 9.05 (8.93) 122-123 m 5 5 CO₂BuCO₂Bu cyclo-Pentyl cyclo-Pentyl A 68^(b) D 83 70.37 (70.02) 9.72 (9.71)78-85 n 7 7 CO₂Et CO₂Et Me Me Me Me A 57 D 74 69.41 (69.31) 10.73(10.62) 74-77^(a)See ref 6.^(b)Purity >90%.^(c)KOH, EtOH, rt.

TABLE 3 Synthesis of 108a-b. Yield Compound m R R1 R2 (%) 8a 4 Et Me Me67 8b 5 Et Me Me 61

t-Butyl 1-(4-bromo-butyl)-cyclopropanecarboxylate (103b). Under a N₂atmosphere at −60° C., a solution of t-butyl cyclopropanecarboxylate(80.05 g, 0.507 mol) and 1,4-dibromobutane (219.3 g, 1.01 mol) in dryTHF (800 mL) was added dropwise to a solution of LDA (2 M inTHF/heptane/ethylbenzene, 380 mL, 0.76 mol) in 1.5 h. Stirring wascontinued for 5 h, during which the reaction mixture was allowed toslowly reach rt. After that, the reaction mixture was poured intosaturated aqueous NH₄Cl (1 L). The organic layer was separated andconcentrated in vacuo to a smaller volume. The aqueous layer wasextracted with Et₂O (3×200 mL). The combined organic layers were washedwith saturated aqueous NH₄Cl (2×400 mL) and brine (400 mL) and dried.The remaining residue was purified by fractional distillation underreduced pressure to give 103b (51.4 g, 94% pure by GC, 34%) as aslightly yellow oil. bp: T=93-96° C. (p=0.075-0.087 Torr). ¹H NMR: δ3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1 Hz, 2H), 1.65-1.46 (m, 4H),1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H), 0.60 (q, J=3.5 Hz, 2H). ¹³C NMR: δ174.0, 79.8, 33.6, 33.2, 32.8, 27.9 (3×), 26.3, 23.9, 15.1 (2×). HRMScalcd for C₁₂H₂₁BrO₂ (MH⁺): 277.0803, found: 277.0807.

Butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (103c). Compound 103cwas prepared, likewise the procedure described for 103b, starting frombutyl cyclopentanecarboxylate (Payne, G. B. et al. J. Org. Chem., 1957,22, 1680-1682) (80.0 g, 0.42 mol), 1,4-dibromobutane (183.3 g, 0.84 mol)and LDA (2 M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) to give,after purification by fractional distillation under reduced pressure,103c (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C.(p=0.040-0.051 Torr). ¹H NMR: δ 4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m,8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). ¹³C NMR: δ 177.6, 64.1,53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6.HRMS calcd for C₁₄H₂₅BrO₂ (M⁺): 304.1038, found: 304.1042.

Butyl 1-(5-bromo-pentyl)-cyclopentanecarboxylate (103f). Compound 103fwas prepared, likewise the procedure described for 103b, starting frombutyl cyclopentanecarboxylate (40.2 g, 0.236 mol), 1,5-dibromopentane(64 mL, 0.45 mol) and LDA (2 M in THF/heptane/ethylbenzene, 200 mL, 0.40mol) to give, after purification by fractional distillation underreduced pressure, 3f (49.1 g, 93% pure by GC, 61%) as a bright yellowliquid. bp: T=123° C. (p=0.001 Torr). ¹H NMR: δ 4.06 (t, J=6.6 Hz, 2H),3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79 (quintet, J=7.1 Hz,2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H), 1.28-1.17 (m, 2H), 0.94 (t,J=7.4 Hz, 3H). ¹³C NMR: δ 177.7, 64.0, 54.0, 39.0, 36.0 (2×), 33.6,32.5, 30.7, 28.5, 25.1, 24.8 (2×), 19.1, 13.6. HRMS calcd for C₁₅H₂₇BrO₂(M⁺): 318.1195, found: 318.1192.

Ethyl 2,2-dimethyl-9-bromononanoate (103g). Under a N₂ atmosphere at 0°C., LDA (2 M in THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol) was addeddropwise to a mixture of ethyl isobutyrate (3.5 mL, 25.9 mmol) and1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL) in 1.5 h,while keeping the temperature below 5° C. After 3 h, the mixture waspoured into ice-cold saturated aqueous NH₄Cl (150 mL). The layers wereseparated and the aqueous phase was extracted with Et₂O (3×100 mL). Thecombined organic layers were washed with aqueous HCl (1 M, 100 mL),saturated aqueous NaHCO₃ (100 mL) and brine (100 mL) and dried. Theremaining residue was purified by column chromatography(heptane:EtOAc=40:1) twice to give 103g (3.42 g, 45%) as a colorlessliquid. ¹H NMR: δ 4.11 (q, J=7.2 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.85(quintet, J=6.9 Hz, 2H), 1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20(m, 6H), 1.24 (t, J=7.2 Hz, 3H), 1.15 (s, 6H). ¹³C NMR: δ 177.8, 60.0,42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2×), 24.7, 14.1. HRMScalcd for C₁₃H₂₅BrO₂ (M⁺): 292.1038, found: 292.1034.

t-Butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (104a). Compound104a was prepared, likewise the procedure described for 103b, startingfrom t-butyl cyclopropanecarboxylate (Kohlrausch, K. W. F. et al. Z.Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285) (12.5 g, 88 mmol),1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and LDA (prepared from BuLi(2.5M in hexanes, 37 mL, 92.5 mmol) and iPr₂NH (12.3 mL, 88 mmol,distilled from NaOH)) to give, after purification by fractionaldistillation under reduced pressure, 104a (10.73 g 52%) as a colorlessoil. bp: T=57-61° C. (p=0.001 mbar). ¹H NMR: δ 3.52 (t, J=6.6 Hz, 2H),1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42(s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). ¹³CNMR: δ 173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×).HRMS calcd for C₁₂H₂₂ClO₂ (MH⁺): 233.1308, found: 233.1308.

Ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (104b). Compound 104bwas prepared, likewise the procedure described for 104c, starting fromLDA (prepared from BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) and iPr₂NH(18.52 mL, 132 mmol, distilled from NaOH)), ethyl1-cyclobutanecarboxylate (Török, B. et al. J. Chem. Soc. Perkin Trans.1, 1993, 7, 801-804) (14.05 g, 110 mmol) (the resulting mixture wasallowed to warm to 0° C. and cooled again to −60° C.) and1-bromo-4-chlorobutane (19.1 mL, 165 mmol) to give, after purificationby fractional distillation under reduced pressure, 104b (20.53 g, 86%)as a thin, colorless oil. bp: T=64-71° C. (p=0.001 Torr). ¹H NMR: δ 4.13(q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70(m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). ¹³C NMR: δ 176.6,60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4.

t-Butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c). Under an Aratmosphere at 0° C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol) was addeddropwise to a solution of iPr₂NH (27.2 mL, 194 mmol, distilled fromNaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirredfor 30 min, cooled to −70° C. and then, t-butyl cyclopropanecarboxylate(25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixturewas allowed to warm up to −35° C., cooled again to −70° C. and then1-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in15 min. The reaction mixture was allowed to reach −5° C., stirred for 3h, poured into a mixture of ice (100 mL), H₂O (100 mL), brine (200 mL)and aqueous HCl (2 M, 200 mL) and extracted with Et₂O (2×300 mL). Thecombined organic layers were washed with a mixture of brine andsaturated aqueous NaHCO₃ (10:1, 300 mL) and dried. The remaining oil waspurified by fractional distillation under reduced pressure to give 104c(31.5 g, 73%) as a colorless liquid. bp: T=67-74° C. (p=0.001 mbar). ¹HNMR: 3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48-1.38 (m,6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9Hz, 2H). ¹³C NMR: δ 174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3×), 27.20,27.17, 24.3, 15.4 (2×). HRMS calcd for C₁₃H₂₄ClO₂ (MH⁺): 247.1465,found: 247.1465.

t-Butyl 1-(4-iodobutyl)-1-cyclopropanecarboxylate (105a). To a solutionof t-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (104a, 10.6 g,45.7 mmol) in 2- butanone (50 mL) was added NaI (8.23 g, 54.5 mmol). Thereaction mixture was stirred under reflux overnight, diluted with Et₂O(100 mL), washed with a mixture of H₂O (100 mL) and aqueous Na₂S₂O₄ (0.5M, 10 mL) and brine (50 mL) and dried to give 105a (14.8 g, 94% pure byGC, 94%) as a slightly yellow liquid. ¹H NMR: δ 3.18 (t, J=6.9 Hz, 2H),1.76 (quintet, J=7.1 Hz, 2H), 1.62-1.45 (m, 4H), 1.43 (s, 9H), 1.12 (dd,J=6.7 Hz, 3.8 Hz, 2H), 0.60 (dd, J=6.6 Hz, 3.9 Hz, 2H). ¹³C NMR: δ173.9, 80.0, 33.8, 33.3, 28.9, 28.2 (3×), 24.2, 15.5 (2×), 7.2. HRMScalcd for C₁₂H₂₁IO₂ (M⁺): 324.0587, found: 324.0587.

Ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (105b). Compound 105b wasprepared, likewise the procedure described for 5a, starting from ethyl1-(4-chlorobutyl)-1-cyclobutanecarboxylate (104b, 21.21 g, 97.0 mmol)and NaI (19.07 g, 127 mmol) to give 105b (29.91 g, 99%) as a slightlyyellow oil. ¹H NMR: δ 4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H),2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1Hz, 3H). ¹³C NMR: δ 176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0,15.7, 14.5, 6.8.

t-Butyl 1-(5-iodopentyl)-1-cyclopropanecarboxylate (105c). To a solutionof t-butyl 1-(5-chloropentyl)-1-cyclopropanecarboxylate (104c, 31.5 g,128 mmol) in 2-butanone (150 mL) was added NaI (24.9 g, 166 mmol). Thereaction mixture was stirred under reflux for 24 h, diluted with heptane(220 mL) and filtered through a layer of silicagel (˜2 cm) in aglassfilter. The residue was eluted with a mixture of heptane and EtOAc(3:1, 5×100 mL). The combined filtrate and elutes were evaporated invacuo to give 5c (42.3 g, 99%) as a slightly yellow liquid. ¹H NMR: δ3.18 (t, J=7.1 Hz, 2H), 1.82 (quintet, J=7.1 Hz, 2H), 1.48-1.33 (m, 6H),1.42 (s, 9H), 1.10 (dd, J=6.8 Hz, Hz, 2H), 0.58 (dd, J=6.6, 3.9 Hz, 2H).¹³C NMR: δ 174.0, 79.9, 34.1, 33.6, 30.8, 28.2 (3×), 26.8, 24.3, 15.4(2×), 7.4. HRMS calcd for C₁₃H₂₃IO₂ (M⁺): 338.0743, found: 338.0743.

{7-Ethoxy-6,6-dimethyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl}(methylidyne)ammonium(108a). To a mixture of K₂CO₃ (13.18 g, 95.6 mmol) and Bu₄NI (2.35 g,6.36 mmol) in dry DMF (50 mL) was added a solution of 103a (24.00 g,95.6 mmol) and TosMIC (12.41 g, 63.7 mmol) in dry DMF (50 mL) in 20 minunder a N₂ atmosphere while stirring vigorously. After 4 d, H₂O (100 mL)was added dropwise while keeping the temperature below 25° C. by coolingwith an ice-bath. The resulting mixture was extracted with Et₂O (3×200mL). The combined organic layers were washed with saturated aqueousNaHCO₃ (2×200 mL) and dried. The remaining residue was purified bycolumn chromatography (silica; heptane:EtOAc=6:1; a layer of NaHCO₃ wasput on the base of the column) to give 108a (15.68 g, 42.8 mmol, 67%) asa slightly yellow oil which slowly solidified on standing. An analyticalsample was obtained after recrystallization (0.43 g) from iPr₂O/heptaneat ˜4° C. to give 108a (0.30 g) as a white solid. mp=38-39° C. ¹H NMR: δ7.84 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H), 4.43 (dd, J=3.3, 10.8Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 2.48 (s, 3H), 2.23-2.12 (m, 1H),1.90-1.77 (m, 1H), 1.66-40 (m, 4H), 1.38-1.22 (m, 2H), 1.24 (t, J=7.1Hz, 3H), 1.15 (s, 6H). ¹³C NMR: δ 177.3, 164.6, 146.3, 131.0, 129.93(2×), 129.87 (2×), 72.8, 60.4, 42.2, 40.2, 28.4, 26.0, 25.35, 25.30,24.2, 22.0, 14.5.

{8-Ethoxy-7,7-dimethyl-1-[(4-methylphenyl)sulfonyl]-8-oxooctyl}(methylidyne)ammonium(108b). Under a N₂ atmosphere, TosMIC (10.01 g, 51.3 mmol) and 103e(20.41 g, 77.0 mmol) were dissolved in dry DMF (100 mL) and BU4NI (1.89g, 5.12 mmol) and K₂CO₃ (10.62 g, 76.8 mmol) were added while stirringvigorously. After 5 d, the reaction mixture was poured in an ice/H₂Omixture (500 mL) and extracted with Et₂O (1×200 mL, 2×100 mL). Thecombined organic layers were washed with brine (2×50 mL) and dried. Theremaining residue was purified by column chromatography (silica,heptane:EtOAc=3:1) to give in order of elution 103e (5.67 g, 90% pure byGC), an impure batch of 108b (0.94 g), and pure 108b (11.83 g, 61%) as acolorless oil. ¹H NMR: δ 7.86 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H),4.45 (dd, J=10.9, 3.5 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 2.49 (s, 3H),2.22-2.11 (m, 1H), 1.90-1.77 (m, 1H), 1.67-1.57 (m, 1H), 1.53-1.42 (m,3H), 1.24 (t, J=7.2 Hz, 3H), 1.39-1.20 (m, 4H), 1.15 (s, 6H). ¹³C NMR: δ177.8, 164.8, 146.5, 131.1, 130.1 (2×), 130.0 (2×), 72.8, 60.2, 42.0,40.3, 29.0, 28.3, 25.12, 25.06 (2×), 24.5, 21.7, 14.2. HRMS calcd forC₂₀H₂₉NNaO₄S (MNa⁺): 402.1715, found: 402.1736.

General Procedures for Alkylation of TosMIC

Method A. t-Butyl1-[9-[1-(tert-butoxycarbonyl)cyclopropyl]-5-oxononyl]-1-cyclopropanecarboxylate(106d). Under a N₂ atmosphere, NaH (60% (^(w)/w) in mineral oil, 2.91 g,72.8 mmol) was added portionwise to a solution of TosMIC (5.85 g, 30.0mmol) and Bu₄NI (1.10 g, 2.98 mmol) in dry DMSO (100 mL) while stirringvigorously and cooling with a water bath. After 10 min, 103b (16.56 g,94% pure by GC, 56.2 mmol) was added dropwise in 20 min and stirring wascontinued for 1 h and 50 min. Then, H₂O (100 mL) was added dropwise andthe resulting mixture was extracted with Et₂O (3×100 mL). The combinedorganic layers were washed with brine (2×100 mL) and dried. Theremaining oil was purified by column chromatography (silica,heptane:EtOAc=6:1) to give t-butyl1-{9-[1-(t-butoxycarbonyl)cyclopropyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopropanecarboxylate(10.00 g) as a slightly yellow oil.

Acidic hydrolysis of alkylated TosMIC intermediate. The above mentionedoil (10.00 g) was dissolved in CH₂Cl₂ (200 mL) and conc aqueous HCl (4mL) was added. After stirring vigorously for 1 h, H₂O (100 mL) was addedand the layers were separated. The aqueous phase was extracted withCH₂Cl₂ (100 mL) and the combined organic layers were washed withsaturated aqueous NaHCO₃ (3×100 mL) and dried. The remaining residue waspurified by column chromatography (silica, heptane:EtOAc=10:1) to give106d (5.80 g, 49%) as a colorless oil. ¹H NMR: δ 2.39 (t, J=7.3 Hz, 4H),1.63-1.38 (m, 30H), 1.10 (dd, J=6.6, 3.9 Hz, 4H), 0.59 (dd, J=6.7,3.9Hz, 4H). ¹³C NMR: δ 211.1, 174.4 (2×), 79.9 (2×), 42.7 (2×), 33.9 (2×),28.0 (6×), 27.4 (2×), 24.1 (2×), 24.0 (2×), 15.2 (4×). HRMS calcd forC₂₅H₄₃O₅ (MH⁺): 423.3111, found: 423.3111.

Method B. Ethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate(106f). Under a N₂ atmosphere at 0° C., KOtBu (8.61 g, 76.7 mmol) wasadded portionwise to a solution of 105b (24.83 g, 80.1 mmol) and TosMIC(7.26 g, 36.4 mmol) in N,N-dimethylacetamide (DMAc, 150 mL). After 30min, the reaction mixture was allowed to warm to rt, stirred for 1.5 hand diluted with DMAc (10 mL). Then, 105b (2.01 g, 6.5 mmol) and KOtBu(0.81 g, 7.2 mmol) were added followed by another portion of 105b (1.00g, 3.2 mmol) and KOtBu (0.86 g, 7.7 mmol) after 1 h. After 1 h, thereaction mixture was poured into a mixture of Et₂O (700 mL) and aqueousNaCl (10%, 500 mL) and the layers were separated. The organic layer waswashed with brine (1×500 mL, 1×300 mL) and dried. The remaining residuewas purified by column chromatography (silica, heptane:EtOAc=6:1) togive ethyl1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl-1-cyclobutanecarboxylate(18.35 g) as a slightly yellow oil. Part of this oil (15.62 g, 27.9mmol) was hydrolyzed with conc aqueous HCl (75 mL) according to theprocedure described for 106d to give, after purification by columnchromatography (silica, heptane:EtOAc=6:1), 106f (9.99 g, 82%) as aslightly yellow liquid, after evaporation from CH₂Cl₂ (100 mL). ¹H NMR:δ 4.12 (q, J=7.1 Hz, 4H), 2.44-2.32 (m, 8H), 1.93-1.79 (m, 8H),1.77-1.72 (m, 4H), 1.55 (quintet, J=7.5 Hz, 4H), 1.25 (t, J=7.1 Hz, 6H),1.21-1.10 (m, 4H). ¹³C NMR: δ 210.2, 176.7 (2×), 60.2 (2×), 47.6 (2×),42.6 (2×), 37.9 (2×), 30.1 (4×), 24.7 (2×), 24.1 (2×), 15.7 (2×), 14.4(2×). HRMS calcd for C₂₃H₃₈O₅ (M⁺): 394.2719, found: 394.2703.

Method C. Ethyl13-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-8-oxotridecanoate(106k). Under a N₂ atmosphere at 0° C., a solution of 108b (28.4 g, 75.0mmol) in N,N-dimethylacetamide (DMAc, 125 mL) followed by a solution of105c (25.4 g, 75.0 mmol) in DMAc (125 mL) were added dropwise in 60 and30 min, respectively to a solution of KOtBu (8.83 g, 79.0 mmol) in DMAc(250 mL). The mixture was allowed to reach rt and stirring was continuedfor 2 h. Then, the reaction mixture was quenched by the dropwiseaddition of H₂O (250 mL) while cooling with an ice-bath. The resultingmixture was extracted with Et₂O (3×250 mL) and the combined organiclayers were washed with brine (2×250 mL) and dried to give a yellow oil(43.02 g). Part of this oil (42.50 g) was hydrolyzed with conc aqueousHCl (34 mL) according to the procedure described for 106d to give, afterpurification by column chromatography (silica, heptane:EtOAc=8:1), 106k(19.0 g, 95% pure by ¹H NMR, 57%) as a slightly yellow oil. ¹H NMR: δ4.09 (q, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H),1.62-1.35 (m, 10H), 1.41 (s, 9H), 1.30-1.21 (m, 6H), 1.24 (t, J=7.2 Hz,3H), 1.14 (s, 6H), 1.09 (dd, J=6.6, 3.9 Hz, 2H), 0.58 (dd, J=6.3, 3.6Hz, 2H). ¹³C NMR: δ 210.8, 177.6, 174.1, 79.8, 60.2, 42.9. 42.8, 42.2,40.6, 34.1, 29.8, 29.6, 28.2 (3×), 27.6, 25.3 (2×), 24.9, 24.3, 23.9,23.8, 15.3 (2×), 14.4.

Ethyl 11-[1-(t-butoxycarbonyl)cyclopropyl]-2,2-dimethyl-7-oxoundecanoate(106c). Compound 6c was prepared likewise Method C starting from 108a(20.5 g, 55.9 mmol), 105a (18.11 g, 55.9 mmol) and KOtBu (6.57 g, 58.7mmol) to give a yellow oil (31.79 g). Part of this oil (30.63 g) wastreated with conc aqueous HCl (23 mL), as described for 106d, to give,after purification by column chromatography (silica,heptane:EtOAc=40:1), 106c (9.83 g, >90% pure by NMR, 43%) as a colorlessoil. ¹H NMR: δ 4.09 (q, J=7.2 Hz, 2H), 2.38 (t, J=7.2 Hz, 4H), 1.62-1.35(m, 10H), 1.41 (s, 9H), 1.26-1.17 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14(s, 6H), 1.09 (dd, J=6.9, 4.2 Hz, 2H), 0.59 (dd, J=6.3, 3.6 Hz, 2H). ¹³CNMR: δ 210.5, 177.4, 174.0, 79.8, 60.2, 42.8, 42.6, 42.1, 40.5, 34.0,28.2 (3×), 27.5, 25.2 (2×), 24.7, 24.3, 24.2, 24.1, 15.3 (2×), 14.4.

Ethyl 11-[1-(ethoxycarbonyl)cyclobutyl]-2,2-dimethyl-7-oxoundecanoate(106e). Compound 106e was prepared likewise Method C starting from 108a(11.01 g, 30.1 mmol), 105b (10.28 g, 33.1 mmol) and KOtBu (4.06 g, 36.2mmol) to give, after purification by column chromatography (silica,heptane:EtOAc=6:1; a layer of NaHCO₃ was put on the base of the column),ethyl1-[11-ethoxy-5-isocyano-10,10-dimethyl-5-[(4-methylphenyl)sulfonyl]-11-oxoundecyl]-1-cyclobutanecarboxylate(14.11 g) as a colorless oil. Part of this oil (13.86 g, 25.3 mmol) wastreated with conc aqueous HCl (50 mL), as described for 106d, to givecrude 106e, which was stirred up in heptane (50 mL) and the resultingprecipitate was filtered off and washed with heptane (3×50 mL). Thecombined filtrates were washed with aqueous NaOH (1M, 2×50 mL) and brine(50 mL) and dried to give 106e (9.44 g, >90% pure by ¹H NMR, 75%) as aslightly yellow oil. ¹H NMR: δ 4.12 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1Hz, 2H), 2.50-2.29 (m, 2H), 2.37 (t, J=7.4 Hz, 4H), 1.95-1.70 (m, 6H),1.61-1.44 (m, 6H), 1.30-1.09 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (t,J=7.1 Hz, 3H), 1.14 (s, 6H). ¹³C NMR: δ 210.1, 177.3, 176.6, 60.1 (2×),47.5, 42.57 (2×), 42.1, 40.4, 37.8, 30.0 (2×), 25.2 (2×), 24.7, 24.6,24.2, 24.1, 15.7, 14.4, 14.3.

Butyl1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate(106g). Compound 106g was prepared likewise Method A starting fromTosMIC (6.58 g, 33.0 mmol), Bu₄NI (1.31 g, 3.55 mmol), NaH (60% (^(w)/w)in mineral oil, 3.20 g and 0.56 g after 2 h, 80.0 and 14.0 mmol) and103c (21.59 g, 67.2 mmol) to give, after purification by columnchromatography (silica, heptane:EtOAc=8:1), butyl1-{9-[1-(butoxycarbonyl)cyclopentyl]-5-isocyano-5-[(4-methylphenyl)sulfonyl]nonyl}-1-cyclopentanecarboxylateas a yellow oil (13.38 g). This oil (13.38 g) was treated with concaqueous HCl (75 mL), as described for 106d, to give, after purificationby column chromatography (silica, heptane:EtOAc=10:1), 106g (9.05 g,56%) as a slightly yellow liquid. ¹H NMR: δ 4.05 (t, J=6.5 Hz, 4H), 2.36(t, J=7.5 Hz, 4H), 2.14-2.05 (m, 4H), 1.65-1.32 (m, 28H), 1.24-1.16 (m,4H), 0.96 (t, J=7.2 Hz, 6H). ¹³C NMR: δ 210.8, 177.8 (2×), 64.1 (2×),54.0 (2×), 42.6 (2×), 39.0 (2×), 36.0 (4×), 30.7 (2×), 25.6 (2×), 24.9(4×), 24.1 (2×), 19.1 (2×), 13.6 (2×). HRMS calcd for C₂₉H₅₀O₅ (M⁺):478.3658, found 478.3663.

Tetraethyl 7-oxo-2,2,12,12-tridecanetetracarboxylate (106h). Compound106h was prepared likewise Method A starting from TosMIC (10.63 g, 53.4mmol), Bu₄NI (3.99 g, 10.7 mmol), NaH (60% (^(w)/w) in mineral oil, 4.27g, 107 mmol) and 103d (30.0 g, 97.0 mmol) to give, after filtrationthrough silica (elute: heptane:EtOAc=2:1),7-ethoxy-6-(ethoxycarbonyl)-1-[6-ethoxy-5-(ethoxycarbonyl)-5-methyl-6-oxohexyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxoheptyl(methylidyne)ammonium(27.9 g) as a yellow oil. Part of this oil (26.9 g) was treated withconc aqueous HCl (50 mL), as described for 106d, to give, afterpurification by column chromatography (silica, heptane:EtOAc=4:1), 106h(16.21 g, 71%) as a yellow oil. ¹H NMR: δ 4.17 (q, J=7.1 Hz, 8H), 2.40(t, J=7.4 Hz, 4H), 1.87-1.82 (m, 4H), 1.58 (quintet, J=7.4 Hz, 4H), 1.38(s, 6H), 1.28-1.18 (m, 4H), 1.25 (t, J=7.2 Hz, 12H). ¹³C NMR: δ 210.0,172.0 (4×), 60.8 (4×), 53.3 (2×), 42.1 (2×), 35.0 (2×), 23.6 (4×), 19.5(2×), 13.8 (4×). HRMS calcd for C₂₅H₄₃O₉ (MH⁺): 487.2907, found:487.2944.

t-Butyl1-11-[1-(t-butoxycarbonyl)cyclopropyl]-6-oxoundecyl-1-cyclopropanecarboxylate(1061). Compound 1061 was prepared likewise Method B starting fromTosMIC (13.84 g, 70.9 mmol), 105c (24.0 and 24.0 g after 1.5 h in 15min, 71.0 and 71.0 mmol) and KOtBu (8.35 and 8.35 g after 1.5 h, 74.6and 74.6 mmol) to give, after dissolving the crude product in EtOAc (100mL) and filtration through silica (elute: heptane:EtOAc=1:1, 5×80 mL) anoil (42.38 g). This oil (42.38 g) was treated with conc aqueous HCl(11.4 mL), as described for 106d, to give, after purification by columnchromatography (silica, heptane:EtOAc=12:1), 1061(16.3 g, >90% pure by¹H NMR, 46%) as a colorless oil. ¹H NMR: δ 2.37 (t, J=7.4 Hz, 4H),1.62-1.49 (quintet, J=7.4 Hz, 4H), 1.48-1.36 (m, 8H), 1.41 (s, 18H),1.33-1.20 (m, 4H) 1.09 (dd, J=6.5, 3.8 Hz, 4H), 0.58 (dd, J=6.6, 3.9 Hz,4H). ¹³C NMR: δ 210.9, 174.1 (2×), 79.8 (2×), 42.9 (2×), 34.1 (2×), 29.6(2×), 28.2 (6×), 27.7 (2×), 24.4 (2×), 24.0 (2×), 15.4 (4×).

Butyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-oxoundecyl}-1-cyclopentanecarboxylate(106m). Compound 106m was prepared likewise Method A starting fromTosMIC (12.48 g, 62.6 mmol), Bu₄NI (2.56 g, 6.93 mmol), NaH (60%(^(w)/w) in mineral oil, 7.55 g and 1.20 g after 2 h, 189 mmol and 30.0mmol) and 103f (44.46 g, 93% pure by GC, 129 mmol) to give, afterpurification by column chromatography (silica, heptane/EtOAc=8:1), butyl1-{11-[1-(butoxycarbonyl)cyclopentyl]-6-isocyano-6-[(4-methylphenyl)sulfonyl]undecyl}-1-cyclopentanecarboxylateas a yellow oil (32.79 g). This oil (32.79 g) was treated with concaqueous HCl (150 mL), as described for 106d, to give, after purificationby column chromatography (silica, heptane:EtOAc=6:1), 106m (24.11 g, 90%pure by ¹H NMR, 68%) as a slightly yellow liquid. ¹H NMR: δ 4.06 (t,J=6.6 Hz, 4H), 2.36 (t, J=7.4 Hz, 4H), 2.15-2.06 (m, 4H), 1.65-1.52 (m,20H), 1.49-1.32 (m, 8H), 1.27-1.19 (m, 8H), 0.94 (t, J=7.4 Hz, 6H). ¹³CNMR: δ 210.9, 177.6 (2×), 63.8 (2×), 54.0 (2×), 42.5 (2×), 38.9 (2×),35.8 (4×), 30.6 (2×), 29.5 (2×), 25.6 (2×), 24.7 (4×), 23.4 (2×), 19.0(2×), 13.5 (2×). HRMS calcd for C₃₁H₅₄O₅ (M⁺): 506.3971, found:506.3981.

Diethyl 10-oxo-2,2,18,18-tetramethyl-nonadecanedioate (106n). Compound106n was prepared likewise Method A starting from TosMIC (2.43 g, 12.5mmol), Bu₄NI (0.462 g, 1.25 mmol), NaH (60% (^(w)/w) in mineral oil,1.21 g, 30.3 mmol) and 103g (7.65 g, 88% pure by GC, 23.0 mmol) to give,after purification by column chromatography (silica, heptane:EtOAc=6:1),{10-ethoxy-1-(9-ethoxy-8,8-dimethyl-9-oxononyl)-9,9-dimethyl-1-[(4-methylphenyl)sulfonyl]-10-oxodecyl}(methylidyne)ammonium(5.41 g) as a yellow oil. Part of this oil (5.03 g) was treated withconc aqueous HCl (30 mL), as described for 106d, to give, afterpurification by column chromatography (silica, heptane:EtOAc=7:1), 106n(3.21 g, 57%) as a colorless oil. ¹H NMR: δ 4.11 (q, J=7.2 Hz, 4H), 2.37(t, J=7.4 Hz, 4H), 1.57-1.46 (m, 8H), 1.28-1.23 (m, 16H), 1.24 (t, J=7.1Hz, 6H), 1.15 (s, 12H). ¹³C NMR: δ 211.5, 178.0 (2×), 60.08 (2×), 60.07(2×), 42.7 (2×), 42.1 (2×), 40.7 (2×), 29.9 (2×), 29.21 (2×), 29.15(2×), 25.1 (2×), 24.8 (2×), 23.8 (2×), 14.2 (2×). HRMS calcd forC₂₇H₅₀O₅ (M⁺): 454.3658, found: 454.3663.

General Procedures for Ester Hydrolysis

Method D.1-[9-(1-Carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid(107f). LiOH.H₂O (3.94 g, 93.9 mmol) and H₂O (30 mL) were added to asolution of 106f (9.20 g, 23.3 mmol) in EtOH (90 mL) and the resultingmixture was stirred at reflux temperature for 17 h, allowed to cool tort and concentrated in vacuo to a smaller volume. H₂O (150 mL) was addedand the resulting mixture was extracted with Et₂O (50 mL), acidifiedwith aqueous HCl (6 M, 25 mL) and extracted with Et₂O (1×100 mL, 2×50mL). The latter organic layers were combined, washed with brine (50 mL)and dried. The remaining residue was recrystallized from iPr₂O/heptaneto give 7f (4.41 g, 56%) as small, white granules. mp 69-70° C. ¹H NMR:δ 11.2 (br s, 2H), 2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84(m, 8H), 1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m,4H). ¹³C NMR: δ 210.6, 183.4 (2×), 47.6 (2×), 42.7 (2×), 37.8 (2×), 30.1(4×). 24.7 (2×), 24.1 (2×), 15.7 (233 ). Anal. calcd for C₁₉H₃₀O₅: C,67.43; H, 8.93, found: C, 67.19; H, 8.97.

Method E.1-[9-(1-Carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid(107d). A solution of 106d (5.31 g, 12.6 mmol) in HCO₂H (50 mL) wasstirred for 3 h, evaporated in vacuo and coevaporated from toluene (3×25mL) to give 107d (3.89 g, 99%) as a white solid. An analytical samplewas obtained after recrystallization from iPr₂O/heptane. mp 132-134° C.¹H NMR: (CD₃OD) δ 2.45 (t, J=6.9 Hz, 4H), 1.58-1.39 (m, 12H), 1.14 (dd,J=6.6, 3.7 Hz, 4H), 0.70 (dd, J=6.8, 3.9 Hz, 4H). ¹³C NMR: (CD₃OD) δ214.4, 179.4 (2×), 43.5 (2×), 34.9 (2×), 28.5 (2×), 25.1 (2×), 24.2(2×), 16.2 (4×). Anal. calcd for C₁₇H₂₆O₅: C, 65.78; H, 8.44, found: C,65.40; H, 8.37.

Method F. 11-(1-Carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid(107c). A solution of 106c (9.27 g, >90% pure by NMR, 21.0 mmol) inHCO₂H (50 mL) was stirred for 1.5 h, evaporated in vacuo andcoevaporated from toluene (10 mL). The remaining residue was dissolvedin EtOH:H₂O (2:1, 100 mL) and NaOH (5.33 g, 132 mmol) was added. Theresulting clear solution was warmed to 80° C. and after 5 h, EtOH wasevaporated in vacuo. The remaining solution was diluted with H₂O to ˜100mL, extracted with Et₂O (3×100 mL), acidified to pH˜1 with conc aqueousHCl (˜9 mL) and extracted with Et₂O (3×100 mL). The latter organiclayers were combined and dried. The remaining residue was purified bycolumn chromatography (heptane:EtOAc=2:1 (containing 1% (^(v)/v) HOAC))to give 7c (5.83 g, >90% pure by 1H-NMR, 80%) as a slightly yellow oilwhich turns solid when stored at −18° C. for several days. mp=49-52° C.¹H NMR: (CD₃OD) δ 2.44 (t, J=7.2 Hz, 4H), 1.57-1.42 (m, 10H), 1.30-1.19(m, 2H), 1.17-1.07 (m, 2H), 1.14 (s, 6H), 0.59 (dd, J=6.6, 3.9 Hz, 2H).¹³C NMR: (CD₃OD) δ 213.5, 181.4, 178.9, 43.5, 43.4, 43.0, 41.7, 34.9,28.5, 25.9 (3×), 25.5, 25.2, 24.3, 16.4 (2×).

11-(1-Carboxycyclobutyl)-2,2-dimethyl-7-oxoundecanoic acid (107e).Compound 107e was prepared likewise Method D starting from 106e (8.83g, >90% pure by ¹H NMR, 20.8 mmol) and LiOH.H₂O (2.91 and 1.94 g after18 h, 69.4 and 46.2 mmol) to give, after recrystallized fromiPr₂O/heptane, 7e (5.19 g, 76%) as a white solid. mp=53-55° C. ¹H NMR: δ10.80 (br s, 2H), 2.50-2.35 (m, 2H), 2.39 (t, J=7.2 Hz, 4H), 1.98-1.74(m, 6H), 1.65-1.49 (m, 6H), 1.31-1.11 (m, 4H), 1.18 (s, 6H). ¹³C NMR: δ210.6, 184.3, 183.4, 47.6, 42.7, 42.6, 42.2, 40.5, 37.8, 30.1 (2×), 25.1(2×), 24.8, 24.7, 24.2, 24.1, 15.7.

1-[9-(1-Carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid(107g). Compound 107g was prepared likewise Method D starting from 106g(7.25 g, 15.0 mmol) and LiOH.H₂O (3.21 g, 76.4 mmol) to give 107g (5.46g, 95% pure by ¹H NMR, 94%, mp=99-103° C.) as a white solid. Ananalytical sample was obtained after recrystallization fromiPr₂O/heptane. mp=104-106° C. ¹H NMR: δ 2.39 (t, J=6.9 Hz, 4H),2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). ³C NMR: δ211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9 (4×), 25.7(2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C₂₁H₃₄O₅: C, 68.82; H, 9.35,found: C, 68.78; H, 9.47.

2,12-Di(ethoxycarbonyl)-2,12-dimethyl-7-oxotridecanedioic acid (107h). Asolution of KOH (2.44 g, >85%, >37.0 mmol) in EtOH (80 mL) was added to106h (9.00 g, 18.5 mmol). After stirring for 54 h, another portion ofKOH (1.21 g, >85%, >18.5 mmol) was added and stirring was continued for16 h. The reaction mixture was evaporated in vacuo and Et₂O (250 mL) andH₂O (250 mL) were added. The aqueous layer was separated, acidified withaqueous HCl (2 M, 50 mL) and extracted with Et₂O (250 mL) and CH₂Cl₂(250 mL). The combined organic layers were dried and the remainingresidue was purified by column chromatography (silica,heptane:EtOAc:HOAc=3:2:0.01) and vacuum dried at 50° C. to give 107h(6.43 g, 81%) as a yellow oil. ¹H NMR: δ 10.40 (br s, 2H), 4.21 (q,J=7.1 Hz, 4H), 2.42 (t, J=7.4 Hz, 4H), 1.90-1.84 (m, 4H), 1.59 (quintet,J=7.4 Hz, 4H), 1.43 (s, 6H), 1.32-1.19 (m, 4H), 1.27 (t, J=7.2 Hz, 6H).¹³C NMR: δ 210.9, 177.7 (2×), 172.1 (2×), 61.5 (2×), 53.5 (2×), 42.2(2×), 35.3 (2×), 23.8 (2×), 23.7 (2×), 19.8 (2×), 13.9 (2×). HRMS calcdfor C₂₁H₃₅O₉ (MH⁺): 431.2281, found: 431.2298.

13-(1-Carboxycyclopropyl)-2,2-dimethyl-8-oxotridecanoic acid (107k).Compound 107k was prepared likewise Method F starting from 6k (18.34 g,95% pure by ¹H NMR, 41.0 mmol) to give1-(11-ethoxy-10,10-dimethyl-5,11-dioxoundecyl)-1-cyclopropanecarboxylicacid, which was treated with NaOH (9.68 g, 241 mmol) to give, afterrecrystallized from iPr₂O/heptane, 107k (9.47 g, 68%) as a white solid.The mother liquor was evaporated in vacuo and the remaining residue waspurified by column chromatography (heptane:EtOAc=2:1 (containing 1%(^(v)/v) HOAc)) and recrystallization from iPr₂O/heptane to give asecond batch 107k (2.23 g, 16%) as a white solid. mp=65-66° C. ¹H NMR:(CD₃OD) δ 2.43 (t, J=7.2 Hz, 4H), 1.58-1.42 (m, 10H), 1.35-1.20 (m, 6H),1.14 (s, 6H), 1.15-1.06 (m, 2H), 0.70 (dd, J=6.6, 3.9 Hz, 2H). ¹³C NMR:(CD₃OD) δ 213.8, 181.6, 179.0, 43.6, 43.5, 43.1, 41.9, 35.1, 31.0, 30.6,28.7, 26.2, 25.9 (2×), 25.02, 24.96, 24.4, 16.4 (2×).

1-[11-(1-Carboxycyclopropyl)-6-oxoundecyl]-1-cyclopropanecarboxylic acid(1071). Compound 1071 was prepared likewise Method E starting from 1061(7.50 g, >90% pure by ¹H NMR, 15.0 mmol) to give, after recrystallizedfrom toluene, 1071 (5.06 g, 99%) as colorless crystals. mp=122-123° C.¹H NMR: (DMSO-d6) δ 11.96 (br s, 2H), 2.39 (t, J=7.4 Hz, 4H), 1.50-1.33(m, 12H), 1.25-1.15 (m, 4H), 1.03 (dd, J=6.5, 3.5 Hz, 4H), 0.68 (dd,J=6.6, 3.6 Hz, 4H). ¹³C NMR: (DMSO-d6) δ 209.9, 175.7 (2×), 41.8 (2×),33.2 (2×), 28.8 (2×), 27.2 (2×), 23.3 (2×), 22.9 (233 ), 14.8 (433 ).Anal. calcd for C₁₉H₃₀O₅: C, 67.43; H, 8.93, found: C, 67.20; H, 9.05.

1-[11-(1-Carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid(107m). Compound 107m was prepared likewise Method D starting from 106m(21.03 g, 90% pure by ¹H NMR, 37.3 mmol) and LiOH.H₂O (7.83 g, 187 mmol)to give, after recrystallization from iPr₂O/heptane, 107m (12.15 g, 83%)as white granules. mp=78-85° C. ¹H NMR: δ 2.37 (t, J=7.4 Hz, 4H),2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). ¹³C NMR: δ211.5, 184.8 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2(2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C₂₃H₃₈O₅: C,70.02; H, 9.71, found: C, 70.37; H, 9.72.

10-Oxo-2,2,18,18-tetramethyl-nonadecanedioic acid (107n). Compound 107nwas prepared likewise Method D starting from 106n (11.63 g, 25.6 mmol)and KOH (4.31 g, 77.0 mmol) to give, after recrystallization fromiPr₂O/heptane, 107n (7.56 g, 74%) as white crystals. mp=74-77° C. ¹HNMR: (CD₃OD) δ 2.43 (t, J=7.3 Hz, 4H), 1.57-1.50 (m, 8H), 1.33-1.21 (m,16H), 1.14 (s, 12H). ¹³C NMR: δ 214.5, 182.1 (2×), 43.6 (2×), 43.2 (2×),42.0 (2×), 31.2 (2×), 30.4 (2×), 30.38 (2×), 26.2 (2×), 25.9 (4×), 25.0(2×). Anal. calcd for C₂₃H₄₂O₅: C, 69.31; H, 10.62, found: C, 69.41; H,10.73.

5.2. Synthesis of9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one

2,2-Bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic aciddiethyl ester. Under nitrogen atmosphere, to a solution of2-(6-bromo-2,2-dimethyl-hexyloxy)-tetrahydropyran (17.6 g, 60 mmol) anddiethyl malonate (4.8 g, 30 mmol) in anhydrous DMSO (145 mL) was addedsodium hydride (60% dispersion in mineral oil, 2.88 g, 72 mmol ) undercooling with a water-bath. Tetra-n-butylammonium iodide (2.1 g, 3.6mmol) was then added. The mixture was stirred for 16 h at roomtemperature. Water (140 mL) was added carefully to the reaction mixtureunder cooling with water-bath. The product was extracted with diethylether (3 60 mL) and the combined organic layers were washed with water(4 50 mL) and brine (50 mL). The solution was dried over sodium sulfateand concentrated in vacuo to give2,2-bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic aciddiethyl ester (17.3 g, 82.3%) as an oil. ¹H NMR (300 MHz, CDCl₃/TMS):(ppm) 4.41 (t, J=3.1 Hz, 2H), 4.01 (q, J=7.0 Hz, 4H), 3.82-3.70 (m, 2H),3.50-3.30 (m, 4H), 2.87 (d, J=9.1 Hz, 2H), 1.80-1.35 (m, 16H), 1.30-0.95(m, 18H), 0.88-0.74 (m, 12H). ¹³C NMR (75 MHz, CDCl₃/TMS): (ppm) 172.0,99.1, 76.6, 61.9, 60.9, 57.6, 39.2, 34.3, 32.3, 30.7, 25.7, 25.0, 24.6,24.6, 24.3, 19.5, 14.2.

2,2-Bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester. Asolution of2,2-bis-[5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic aciddiethyl ester (2.92 g, 5mmol) in concentrated HCl (2.4 mL) and water(1.6 mL) was refluxed for 1 h. Ethanol (8.2 mL) was added and thereaction mixture was heated to reflux for 3 h. The reaction mixture wasdiluted with water (20 mL) and extracted with diethyl ether (3×20 mL).The combined organic layers were washed with water (20 mL), brine (20mL), and dried over Na₂SO₄. The solution was concentrated to furnish2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (1.74g, 84%). ¹H NMR (300 MHz, CDCl₃/TMS): (ppm) 4.13 (q, J=7.2 Hz, 4H), 3.25(s, 4H), 2.42 (s, 2H), 1.90-1.75 (m, 4H), 1.30-1.12 (m, 18H), 0.84 (s,12H). ¹³C NMR (75 MHz, CDCl₃/TMS): (ppm) 172.0, 71.7, 60.9, 57.4, 38.2,34.9, 32.1, 24.8, 24.0, 23.7, 14.0.

2,2-Bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid. To a stirredsolution of KOH (4.83 g, 75 mmol) in water (4.2 mL) and ethanol (15 mL)was added 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethylester (15 g). The reaction mixture was heated to reflux for 14 h, thenconcentrated in vacuo, and extracted with chloroform. The aqueous layerwas acidified with HCl until pH 1 and extracted with diethyl ether (3×50mL). The ethereal solution was dried over anhydrous MgSO₄ andconcentrated in vacuo to afford get2,2-bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid (7.8 g, 82.3%) as ayellow solid. ¹H NMR (300 MHz, CD₃OD/TMS): (ppm) 4.86 (s, 4H), 3.22 (s,4H), 1.9-1.8 (m, 4H), 1.36-1.10 (m, 12H), 0.84 (s, 12H). ¹³C NMR (75MHz, CD₃OD/TMS): (ppm) 176.0, 72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5,24.5. Mp.: 178-180 C.

8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic acid.2,2-Bis-(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid was heated to 200 Cusing an oil-bath. This temperature was kept for 30 minutes until theeffervescence ceased.8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic acidwas obtained as an oil (4.04 g, 98%). ¹H NMR (300 MHz, CDCl₃/TMS): (ppm)4.88 (s, 3H), 3.22 (s, 4H), 2.29 (m, 1H), 1.70-1.40 (m, 4H), 1.4-1.1 (m,12H), 0.84 (s, 12H). ¹³C NMR (75 MHz, CDCl₃/TMS): (ppm) 180.5, 72.1,47.1, 39.9, 36.0, 33.8, 29.7, 25.0, 24.6.

9-Hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one.8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic acid(1.0 g, 3.16 mmol) was dissolved in THF (40 mL) and cooled in anice-water bath. Methyl lithium (27 mL) was then added at once. Thereaction was continued for 2 h at 0 C. The reaction mixture was pouredinto dilute hydrochloric acid (5 mL concentrated hydrochloric acid in 60mL water). The organic layer was separated and the aqueous layer wasextracted with diethyl ether (2×50 mL). The combined organic layers weredried over sodium sulfate and concentrated in vacuo to give the crudeproduct (1.0 g). The crude product was purified by column chromatography(hexanes:ethyl acetate=4:1, then 1:1) to give9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one(0.41 g, yield 41%) and7-(1-hydroxy-1-methylethyl)-2,2,12,12-tetramethyltridecan-1,13-diol (0.4g, 38%, not shown) as a by-product. ¹H NMR (300 MHz, CDCl₃/TMS): (ppm)3.46 (s, 4H), 2.65-2.50 (m, 1H), 2.28 (s, 3H), 2.60 (br., 2H), 1.82-1.50(m, 4H), 1.50-1.25 (m, 12H), 1.02 (s, 12H). ¹³C NMR (75 MHz, CDCl₃/TMS):(ppm) 213.4, 71.7, 53.2, 38.3, 34.9, 31.6, 28.7, 28.3, 23.8. HRMS(LSIMS, nba): Calcd. for C₁₉H₃₉O₃ (MH⁺): 315.2899, found: 315.2866.

5.3. Synthesis of Keto-dialkyldicarboxylic Acids bis-Amides

3.1. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acidbis-methylamide

6-[2-(5-Ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid ethyl ester. Under N₂ atmosphere, to a solution of2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (1.0 g,2.70 mmol) and 1,3-propanedithiol (361 mg, 361 L, 3.24 mmol) indichloromethane (20 mL; dried with Aluminum oxide, activated, neutral,Brockmann I) was added boron trifluoride diethyl etherate (100 L) at rt.The reaction mixture was stirred for 3 h, diluted with dichloromethane(100 mL), and extracted with 5% NaOH solution (100 mL) and water (75mL). The organic phase was dried over MgSO₄, concentrated in vacuo, anddried in high vacuo to furnish6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid ethyl ester (1.0 g, 80%) as a yellowish oil. ¹H NMR (300 MHz,CDCl₃/TMS): (ppm): 4.11 (q, 4H, J=7.1), 2.79 (t, 4H, J=5.6), 1.94 (m,2H), 1.84 (m, 4H), 1.54 (m, 4H), 1.39 (m, 4H), 1.24 (t, 6H, J=7.1),1.30-1.20 (m, 4H), 1.16 (s, 12H). ¹³C NMR (75 MHz, CDCl₃/TMS): (ppm):178.08, 60.33, 53.32, 42.27, 40.69, 38.28, 26.14, 25.67, 25.28, 24.71,14.41. HRMS (LSIMS, nba): Calcd. for C₂₄H4₅S₂O₄ (MH⁺): 461.2759, found461.2774.

6-[2-(5-Carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid. A solution of6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide (85%, 750mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was heated underreflux for 3 h. The reaction mixture was diluted with water (100 mL) andacidified to pH 4 with 1 N HCl (8 mL). The emulsion was extracted withdichloromethane (3 75 mL). The combined organic phases were washed withwater (50 mL), dried over MgSO₄, concentrated in vacuo, and dried inhigh vacuo to furnish6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid (730 mg, 95%) as a viscous, yellowish oil. ¹H NMR (300 MHz,CDCl₃/TMS): (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m,4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H). ¹³C NMR (75 MHz,CDCl₃/TMS): (ppm): 185.08, 53.36, 42.28, 40.52, 38.27, 26.18, 25.69,25.23, 25.11, 24.73. HRMS (LSIMS, nba): Calcd. for C₂₀H₃₇O₄S₂ (MH⁺):405.2133, found: 405.2115.

2,2-Dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian-2-yl]-hexanoicacid methylamide. Under N₂ atmosphere, to a solution of6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid (280 mg, 0.67 mmol) and N-hydroxysuccinimide (170 mg, 1.47 mmol) indichloromethane (5 mL; dried with Aluminum oxide, neutral, Brockmann I)was added dicyclohexyl carbodiimide (305 mg, 1.47 mmol). The reactionmixture was stirred and rt for 2 h, the urea was removed by filtrationand washed with dichloromethane (2 mL). The filtrate was concentrated invacuo and dried in high vacuo to give crude6-{2-[5-(2,5-dioxo-pyrrolidin-1-yloxycarbonyl)-5-methyl-hexyl]-[1,3]dithian-2-yl}-2,2-dimethyl-hexanoicacid 2,5-dioxo-pyrrolidin-1-yl ester (500 mg, 125%) as a foamy, yellowoil. Under N₂ atmosphere, to a solution of this crude intermediate (370mg, 0.62 mmol) in anhydrous THF (10 mL) was added a solution ofmethylamine in anhydrous THF (5 mL, 10 mmol, 2.0 M in THF), resulting inthe immediate formation of a white precipitate. The reaction mixture wasstirred at rt for 1.5 h, then diluted with dichloromethane (100 mL), andextracted with saturated NaHCO₃ solution (2 50 mL), water (50 mL), 1 NHCl (50 mL), and saturated NaCl solution. The organic phase wasconcentrated in vacuo and the residue purified by flash chromatography(silica, hexanes/ethyl acetate=50/50, then 25/75, then 0/100) to furnish2,2-dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian-2-yl]-hexanoicacid methylamide (100 mg, 37%) as a colorless oil. Mp.: 104-106 C. ¹HNMR (300 MHz, CDCl₃/TMS): (ppm): 5.92 (m br, 2H), 2.81 (d, 6H, J=4.6),2.78 (m, 4H), 1.94 (m, 2H), 1.82 (m, 4H), 1.52 (m, 4H), 1.37 (m, 4H),1.30-1.14 (m, 4H), 1.17 (s, 12H). ¹³C NMR (75 MHz, CDCl₃/TMS): (ppm):178.46, 53.23, 42.10, 41.32, 38.18, 26.56, 26.08, 25.62, 25.56, 25.16,24.64. HRMS (LSIMS, nba): Calcd. for C₂₂H₄₃N₂S₂O₂ (MH⁺): 431.2766,found: 431.2762.

2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid bis-methylamide. Asuspension of2,2-dimethyl-6-[2-(5-methyl-5-methylcarbamoyl-hexyl)-[1,3]dithian-2-yl]-hexanoicacid methylamide (3.30 g, 7.66 mmol), paraformaldehyde (6.9 g), andAmberlyst 15 (3.85 g) in acetone (100 mL) and water (10 mL) was heatedto reflux for 16 h. The acetone was removed under reduced pressure, thereaction mixture was filtered, and the resin was washed with ethylacetate (3 75 mL). The combined layers were extracted with saturatedNaHCO₃ solution (30 mL) and saturated NaCl solution (30 mL), dried overMgSO₄, and concentrated in vacuo. The residue was purified by flashchromatography (silica; ethyl acetate, then ethyl acetate/ethanol=50/50)to furnish 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acidbis-methylamide (2.45 g, 94%) as a colorless, viscous oil thatsolidified on standing. Mp.: 91.5-93.5 C. ¹H NMR (300 MHz, CDCl₃/TMS):(ppm): 6.05 (d br., 2H, J=4.6), 2.78 (d, 6H, J=4.6), 2.36 (t, 4H,J=7.3), 1.58-1.45 (m, 8H), 1.27-1.12 (m, 4H), 1.15 (s, 12H). ¹³C NMR (75MHz, CDCl₃/TMS): (ppm): 211.50, 178.43, 42.56, 41.99, 41.03, 26.52,25.48, 24.48, 24.20. HRMS (LSIMS, nba): Calcd. for C₁₉H₃₇N₂O₃ (MH⁺):341.2804, found: 341.2804.

5.4. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acidbis-phenylamide

2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acid bis-phenylamide. UnderN₂ atmosphere, to a stirred solution of2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid (3.40 g, 10.9 mmol) inacetonitrile (50 ml) was added N-methyl-morpholine (2.42 g, 2.63 ml,23.9 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (4.20 g, 23.9 mmol)at rt. After 20 h, aniline (5.08 g, 5.0 ml, 54.5 mmol) was added and thereaction mixture was stirred for 26 h. The reaction mixture was dilutedwith ethyl acetate (100 mL) and extracted with ice-cold 1 N HCl (2 100mL), saturated NaCl solution (100 mL), saturated NaHCO₃ solution (2 100mL), and saturated NaCl solution (100 mL). The organic layer was driedover MgSO₄, concentrated in vacuo, and dried in high vacuo to give aviscous, crude oil (4.50 g). 2,2,12,12-Tetramethyl-7-oxo-tridecanedioicacid bis-phenylamide and2,2,12-trimethyl-7-oxo-12-phenylcarbamoyl-tridecanoic acid were isolatedfrom this crude product mixture by flash chromatography (silica;chloroform, then chloroform/acetone=98/2, then chloroform/acetone=95/5).Additional purification of 2,2,12,12-tetramethyl-7-oxo-tridecanedioicacid bis-phenylamide by crystallization (1.0 g oil in ca. 7.5 mlhexanes/chloroform/ethanol=10/4/1) was necessary to give the cleanbis-amide (290 mg, 6%) as a white solid. Mp.: 113-114 C. ¹H NMR (300MHz, CDCl₃): (ppm): 7.52 (d, 2H, J=7.5), 7.50 (s, 2H), 7.27 (t, 4H,J=7.5), 7.07 (t, 2H, J=7.5), 2.34 (t, 4H, J=7.3), 1.64-1.44 (m, 8H),1.34-1.14 (m, 4H), 1.24 (s, 12H). ³C NMR (75 MHz, CDCl₃): (ppm): 211.31,176.08, 138.09, 128.93, 124.28, 120.36, 42.96, 42.84, 41.13, 25.58,24.53, 24.20. HRMS (LSIMS, nba): Calcd. for C₂₉H₄₀N₂O₃ (MH⁺): 465.3118,found: 465.3129.

2,2,12-Trimethyl-7-oxo-12-phenylcarbamoyl-tridecanoic acid. Viscous oil(1.15 g, 25%). ¹H NMR (300 MHz, CDCl₃): (ppm): 8.90 (m br., 1H), 7.57 (sbr, 1H), 7.51 (d, 2H, J=7.9), 7.28 (m, 2H), 7.08 (t, 1H, J=7.3), 2.38(t, 2H, J=7.2), 2.36 (t, 2H, J=7.2 H), 1.53 (m, 8H), 1.34-1.20 (m, 4H),1.26 (s, 6H), 1.16 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): (ppm): 211.54,183.74, 176.28, 138.02, 128.92, 124.35, 120.46, 42.97, 42.55, 42.53,42.06, 41.12, 40.21, 25.56, 25.05, 24.55, 24.52, 24.21, 24.17. HRMS(LSIMS, nba): Calcd. for C₂₃H₃₆NO₄ (MH⁺): 390.2644, found: 390.2650.

5.5. Synthesis of 2,2,12,12-tetramethyl-7-oxo-tridecanedoic acidbis-3-carboxyphenylamide

6-[2-(5-Carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoicacid. A solution of the ester (AL056-97, 870 mg, 1.89 mmol) andpotassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16 mL) andwater (4 mL) was heated under reflux for 3 h. The reaction mixture wasdiluted with water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL).The emulsion was extracted with dichloromethane (3′ 75 mL). The combinedorganic phases were washed with water (50 mL), dried over MgSO4,concentrated in vacuo, and dried in high vacuo to furnish ET06802 (730mg, 95%) as a viscous, yellowish oil. 2.80 (m, 4H), 1.94 (m, 2H), 1.85(m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H).Carboxyl proton resonances were not visible. Estimated purity by 1H NMR:ca. 85%, contains ca. 10% starting material. 185.08, 42,28, 40.52,38.27, 26.18, 25.69, 25.31, 25.23, 25.11, 24.73. Calcd. for C20H37O4S2(MH+): 405.2133, found: 405.2115.

3-(6-2-5-(3-Ethoxycarbonyl-phenylcarbamoyl)-5-methyl-hexyl-1,3dithian-2-yl-2,2-dimethyl-hexanoylamino)-benzoic acid ethyl ester. To asolution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 12.1 g, 68.6mmol) and ET06802 (12.1 g, 29.7 mmol) in THF (50 mL), N-methylmorpholine(NMM, 6.72 g, 66.5 mmol) was added dropwise at −5° C. The reactionmixture was stirred for 4 h at this temperature. Ethyl-3-aminobenzoate(39.2 g, 237.8 mmol) was added at once and the mixture was stirred at rtfor 7 days. The reaction mixture was filtered to remove the solids. Thefiltrate was diluted with ethyl acetate (250 mL) and washed withice-cold 1N HCl (3 180 mL), brine (150 mL), saturated NaHCO3 solution (2300 mL), and brine (200 mL). The organic phase was dried over anhydrousNa2SO4, and concentrated in vacuo to yield a crude solid that was washedwith a solvent mixture of ethyl acetate/hexanes=1/20 (500 mL) to furnishthe product (12.8 g, 61.8%) as a white solid, M.p. 60-70° C. 60-70° C.8.02 (s, 2H), 7.96 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.8 Hz, 2H), 7.59 (s,2H), 7.41 (t, J=6.0 Hz, 2H), 4.38 (q, J=7.2 Hz, 4H), 2.76 (t, J=7.2 Hz,4H), 1.95-1.51 (m, 10H), 1.38 (t, J=7.2 Hz, 6H), 1.40-1.21 (m, 8H), 1.29(s, 12H). 176.35, 166.41, 138.31, 131.21, 129.18, 125.37, 124.84,121.03, 61.31, 53.17, 43.17, 41.44, 38.20, 26.10, 25.64, 25.24, 24.74,14.48. Calcd. for C38H55N2O6S2 (MH⁺): 699.3496, found: 699.3508.

2,2,12,12-Tetramethyl-7-oxo-tridecanedioic acidbis-3-carboethoxy-phenylamide. To a solution of3-(6-2-5-(3-ethoxycarbonyl-phenylcarbamoyl)-5-methyl-hexyl-1,3dithian-2-yl-2,2-dimethyl-hexanoylamino)-benzoic acid ethyl ester (430mg, 0.62 mmol) in dimethoxy ethane (DME, 5 mL) and concentratedhydrochloric acid (0.74 mL), methyl sulfoxide (DMSO, 0.35 mL) was addeddropwise over 5 minutes. The reaction mixture was stirred for 30 minutesat rt. The resulting mixture was slowly poured into saturated sodiumbicarbonate solution (60 mL) and extracted with diethyl ether (2 80 mL).The combined organic layers were washed with water (3 50 mL), dried oversodium sulfate and concentrated in vacuo. The crude product was washedwith hexanes (60 mL) to yield ET07002 (300 mg, 79.0%) as a colorlessoil. 8.05 (s, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.77 (m, 4H), 7.35 (t, J=7.8Hz, 2H), 4.36 (t, J=6.9 Hz, 4H), 2.37 (t, J=7.2 Hz, 4H), 1.62-1.39 (m,10H), 1.46 (t, J=6.9 Hz, 6H), 1.37-1.17 (m, 2H), 1.26 (s, 12H). 211.29,176.33, 166.36, 138.36, 131.07, 129.01, 125.24, 124.86, 121.13, 61.22,43.06, 42.53, 41.05, 25.55, 25.17, 24.53, 24.16, 14.43. Calcd. forC35H49N2O7 (MH+): 609.3534, found: 609.3569.

2,2,12,12-Tetramethyl-7-oxo-tridecanedoic acid bis-3-carboxyphenylamide.To a homogenous solution of KOH (85%, 1.24 g, 18.66 mmol) and2,2,12,12-tetramethyl-7-oxo-tridecanedioic acidbis-carboethoxy-phenylamide (1.9 g, 3.13 mmol) in water (7 ml) andethanol (33 ml) was heated to reflux for 5 h. The ethanol was removedunder reduced pressure. The residue was diluted with water (55 ml). Thesolution was acidified with concd. hcl (4 ml) to ph 1 and extracted withdiethyl ether (2 80 ml). The combined organic layers were washed withbrine (50 ml), dried over anhydrous na2so4 and concentrated in vacuo toyield a crude solid that was washed with hexanes (200 ml) and a solventmixture of ethyl acetate/hexanes=1/40 (200 ml) to furnish a white solid(1.4 g, 81.4% yield, 94.9% pure by hplc), m.p 78-80° C. mp 78-80° C.12.87 (br, 2h), 9.35 (s, 2h), 8.24 (s, 2h), 7.91 (d, j=8.1 hz, 2h), 7.62(d, j=7.8 hz, 2h), 7.42 (t, j=7.8 hz, 2h), 2.35 (t, j=4.5 hz, 4h),1.62-1.50 (m, 4h), 1.45-1.30 (m, 4h), 1.30-1.11 (m, 4h), 1.15 (s, 12h).210.33 , 176.05, 167.29, 139.58, 131.02, 128.63, 124.38, 124.00, 121.14,42.55, 40.36, 38.89, 25.11, 23.99, 23.71. calcd. for c31h41n2o7 (mh):553.2914 , found: 553.2911.

5.6. α,α-Dialkyl or -Arylalkyl-substituted Keto-dialkyldicarboxylicAcids

Long hydrocarbon chain keto-diols and -acids was synthesized asdescribed in Schemes 18 and 19, and Table 4 (Dasseux, J.-L. H. et al.Ketone compounds and compositions for cholesterol management and relateduses. U.S. patent application 20030078239, Oct. 11, 2001). The sidechains connected to the central ketone functionality varied both inlength (n, m=3-7) and in the attached geminal modifying groups (R¹,R²=Me, Ph, 4-Me-C₆H4, 4-iBu-C₆H₄). The majority of target compounds fellin the category of either symmetrical ketodiacids (210b-210g, 210i,210j, Scheme 18) or symmetrical ketodiols (214a-214i, Scheme 19).

TABLE 4 Synthesis of Symmetrical Ketodiacids No. n R¹ R² Yield (%) 209b3 Me Ph 61 209c 4 Me Me 67 209d 4 Me Ph 66 209e 4 Me 4-Me-C₆H₄ 54 209f 4Me 4-iBu—C₆H₄ 82 209g 5 Me Me 61 209i 6 Me Me 40 209j 7 Me Me 61^(a)210b 3 Me Ph 31 210c 4 Me Me 86 210d 4 Me Ph 87 210e 4 Me 4-Me-C₆H₄ 39210f 4 Me 4-iBu—C₆H₄ 86 210g 5 Me Me 57 210i 6 Me Me 57^(b) 210j 7 Me Me74^(a)Intermediate 208j was purified by column chromatography; ^(b)prepared by direct base hydrolysis of 208i.

TABLE 5 Synthesis of Symmetrical Ketodiols. No. n R¹ R² Yield (%) 211i 5Me Me 66 212f 4 Me 4-iBu—C₆H₄ 98 213f 4 Me 4-iBu—C₆H₄ 94 214a 3 Me Me 30214b 3 Me Ph 38 214c 4 Me Me 68 214d 4 Me Ph 61 214e 4 Me 4-Me-C₆H₄ 21214f 4 Me 4-iBu—C₆H₄ 83 214g 5 Me Me 79 214h 5 Me Ph 56 214i 6 Me Me 35

A series of unsymmetrical keto-diols and -acids with chains of differentlengths or with a different substitution pattern (217-219, Scheme 20 and225, 226, Scheme 21) was included in this study as well. In addition,the aryl-bridged compounds 231 and 232 with a benzophenone backbone(Scheme 22) were prepared and examined for comparison.

The key step in the syntheses of all ketones with aliphatic chains wasthe alkylation of tosylmethyl isocyanide (TosMIC) (Possel, O. et al.Tosylmethyl Isocyanide Employed in a Novel Synthesis of Ketones. A NewMasked Formaldehyde Reagent. Tetrahedron Lett. 1977, 17, 4229-4232;Kurosawa, K. et al. Facile Synthesis of [3^(n)]Cyclophanes in whichAromatic Rings are Connected with —CH₂—CO—CH₂— Bridges. TetrahedronLett. 1982, 23, 5335-5338; Yadav, J. S. et al. TosMIC in the Preparationof Spiroacetals: Synthesis of Pheromone Components of Olive Fruit Fly.Tetrahedron Lett. 1990, 31, 6217-6218; van Leusen, D. et al. SyntheticUses of Tosylmethyl Isocyanide (TosMIC). In Organic Reactions, Vol. 57;Overman, L. E., Editor-in-Chief; John Wiley and Sons, Inc.: New York,2001; pp 417-666) with appropriately substituted alkyl bromides (Schemes18-22). These alkyl bromide building blocks were generally synthesizedvia lithiation of commercially available or readily accessible ethylesters 201, 202 (Shiner, V. J., Jr. et al. The Arrhenius Parameters ofthe Deuterium Isotope Rate Effect in a Base-promoted EliminationReaction: Evidence for Proton Tunneling. J. Am. Chem. Soc. 1961, 83,593-598), 203 (Ghosh, S. et al. Ester Enolates from α-Acetoxy Esters.Synthesis of Aryl Malonic and α-Aryl Alkanoic Esters from ArylNucleophiles and α-Keto Esters. J. Org. Chem. 1982, 47, 4692-4702;Chounan, Y. et al. 1,2-Asymmetric Induction in the Conjugate Addition ofOrganocopper Reagents to γ-Aryl α,β-Unsaturated Carbonyl Derivatives.Tetrahedron 2000, 56, 2821-2831), and 204 with lithium diisopropylamidein anhydrous THF in the presence of N,N′-dimethylpropyleneurea (DMPU) at−78° C. followed by subsequent reaction with an α,ω-dibromoalkane (a)Ackerley, N. et al. A Novel Approach to Dual-Acting Thromboxane ReceptorAntagonist/Synthase Inhibitors Based on the Link of1,3-Dioxane-Thromboxane Receptor Antagonists and -Thromboxane SynthaseInhibitors. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al.Thromboxane Synthase Inhibitors. Synthesis and Pharmocological Activityof (R)-, (S)-, and(±)-2,2-Dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)-methoxy]ethoxy]hexanoicAcids. J. Med. Chem. 1987, 30, 1812-1818) of the required chain length(Scheme 18). Thus, bromo esters 205a-205j were obtained in moderate togood yields (Table 4). Reduction of bromo esters with lithiumborohydride and methanol (Brown, H. C. et al. 30. Effect of Cation andSolvent on the Reactivity of Saline Borohydrides for Reduction ofCarboxylic Esters. Improved Procedures for the Conversion of Esters toAlcohols by Metal Borohydrides. J. Org. Chem. 1982, 47, 4702-4708; Soai,K. et al. Mixed Solvents Containing Methanol as Useful Reaction Mediafor Unique Chemoselective Reductions with Lithium Borohydride. J. Org.Chem. 1986, 51, 4000-4005) in refluxing dichloromethane afforded thebromo alcohols 206a-206e, 206g, and 206h in excellent yields andpurities without effecting the bromide moiety. The chemoselectivity ofreduction of similar bromo esters with LiAlH₄ depended on theconditions. In ether at room temperature the bromo alcohol was thesingle product whereas in THF at reflux the reaction gave the alcoholsexclusively. See: Beckwith, A. L. J. et al. Stereochemistry of theReversible Cyclization of ω-Formyl Radicals. J. Org. Chem. 1992, 57,4954-4962. Reduction with lithium aluminum hydride or sodium borohydrideon the other hand was not chemoselective and the reactions were notreproducible. Another chemoselective reducing agent wasdiisobutylaluminum hydride (Brown, H. C. et al. Selective Reductions.30. Effect of Cation and Solvent on the Reactivity of SalineBorohydrides for Reduction of Carboxylic Esters. Improved Procedures forthe Conversion of Esters to Alcohols by Metal Borohydrides. J. Org.Chem. 1982, 47, 4702-4708). Bromo alcohols were treated with3,4-dihydro-2H-pyran and catalytic amounts of p-toluenesulfonic acid(Brown, H. C. et al. Selective Reductions. 30. Effect of Cation andSolvent on the Reactivity of Saline Borohydrides for Reduction ofCarboxylic Esters. Improved Procedures for the Conversion of Esters toAlcohols by Metal Borohydrides. J. Org. Chem. 1982, 47, 4702-4708) togive the THP ethers 207a-207e, 207g, and 207h (Scheme 18, Table 4) inmoderate to good yields.

The synthesis of symmetrical ketodiacids 210b-210g, 210i, and 210j frombromo esters 205b-205g, 205i, and 205j was accomplished employing TosMICmethodology as described above (Scheme 2). Accordingly, TosMIC wasdeprotonated with sodium hydride in either DMSO or in a DMSO/diethylether mixture (Possel, O. et al. Tosylmethyl Isocyanide Employed in aNovel Synthesis of Ketones. A New Masked Formaldehyde Reagent.Tetrahedron Lett. 1977, 17, 4229-4232) at room temperature and thenreacted with suitable bromo esters 205b-205g, 205i, and 205j in thepresence of catalytic amounts of tetrabutylammonium iodide to give thecorresponding dialkylated TosMIC intermediates 208a-208g, 208i, and208j. These alkylations of TosMIC proceeded also without catalyticamounts of NBu₄I, but required a slightly longer reaction time. In mostcases, these intermediates were not purified or characterized butdirectly treated with concd aqueous HCl in dichloromethane (Prato, M. etal. Cleavage of the 1,3-Dithiane Protective Group. Synthesis 1982,679-680) to give ketodiesters 209b-209g, 209i, and 209j in good yieldsafter chromatographic purification (Table 2). Finally, hydrolysis of theester groups with potassium hydroxide in aqueous ethanol and subsequentacidification with concd HCl (steps c, d) provided the target diacids210b-210g, and 210j in variable yields ranging from 31 to 87%. Accordingto a different protocol, ketodiacid 210i was prepared by simultaneoushydrolysis of the tosyl isocyanide and the ester groups in 28i withpotassium hydroxide in aqueous ethanol followed by acidification withdilute sulfuric acid (steps c, e) in 57% yield.

Scheme 3 illustrates three different strategies that were studied forthe synthesis of symmetrical ketodiols. The standard procedure used inmost cases employed the dialkylation protocol of TosMIC as describedabove. Bromo THP ethers 207a-7e, 7g, and 7h were used as electrophilesand the resulting TosMIC intermediates were directly hydrolyzed to givethe ketodiols 214a-214e, 214g, and 214h in acceptable yields afterpurification by column chromatography (Table 3). An alternative pathwaywas elected for the synthesis of ketodiol 214i. In this case,ketodiester 209i was first reduced to triol 211i by treatment withlithium aluminum hydride (66%). Selective oxidation of the secondaryalcohol moiety in 211i with aqueous sodium hypochlorite solution inacetic acid (Stevens, R. V. et al. Further Studies on the Utility ofSodium Hypochlorite in Organic Synthesis. Selective Oxidation of Diolsand Direct Conversion of Aldehydes to Esters. Tetrahedron Lett. 1982,23, 4647-4650; Stevens, R. V. et al. Convenient and InexpensiveProcedure for Oxidation of Secondary Alcohols to Ketones. J. Org. Chem.1980, 45, 2030-2032) then produced 214i in low yield (35%). Betterresults were obtained when the ketone functionality in a ketodiester wasprotected prior to the reduction of the esters. Thus, protection of 209fwith 1,3-propanedithiol and boron trifluoride diethyl etherate (Hatch,R. P. et al. Studies on Total Synthesis of the Olivomycins. J. Org.Chem. 1978, 43, 4172-4177) led to formation of 212f, which wassubsequently reduced with lithium aluminum hydride to 213f. Removal ofthe 1,3-dithiane protective group with DMSO in dimethoxyethane and concdHCl (Prato, M. et al. Cleavage of the 1,3-Dithiane Protective Group.Synthesis 1982, 679-680) afforded ketodiol 214f (63% from 205f). Despitethe superior yields attained, this method was not generally applied forthe synthesis of 214a-214i because of the malodorous reagent involved.

The unsymmetrical ketodiols 217-219 were prepared via the mono-alkylatedTosMIC derivative 215 as a common intermediate (Scheme 21). However,reaction of TosMIC with one equivalent of 207c under the previouslyutilized reaction conditions (NaH and NBu₄I in DMSO) gave a mixture ofmono- and dialkylated products 215 and 216 (For similar successivealkylations of TosMIC with alkyl halides of different chain lengths,see: Rao, A. V. R. et al. A New Route for the Synthesis of1,4-Dicarbonyl Compounds: Synthesis of Jasmone, Dihydrojasmone and aProstaglandin Intermediate. Synth. Commun. 1984, 14, 469-475).Contaminant 216 had to be removed by chromatography to prevent formationof mixtures of 217 or 219, respectively, with 214c in the next step,which were practically impossible to separate; the yield of thispurification was very low (27%). Modification of the conditions (K₂CO₃in DMF) circumvented this problem as 215 was produced in 69% yieldwithout formation of 216, even when an excess of 7c was used. Furtheralkylation of 215 with the respective bromo THP-ethers 207a, 207d, and207g, followed by deprotection with concd HCl in refluxing methanolfurnished the unsymmetrical products 217-219 in respectable yields.

Similar problems with an unwanted dialkylated by-product (208c, Scheme19) were also encountered in the synthetic route to diacids 225 and 226.Alkylation of TosMIC with 205c by treatment with NaH and NBu₄I in DMSOled to a mixture of compounds 220 and 208c that was very difficult toseparate by chromatographic means (For similar mono-alkylations ofTosMIC with long chain bromo esters, see: Johnson, D. W. A Synthesis ofUnsaturated Very Long Chain Fatty Acids. Chem. Phys. Lipids 1990, 56,65-71). As a result, the yield of pure 220 was only 12%. To ensure thecomplete removal of the symmetrical ketodiester 209c that results fromintermediate 208c, compound 220 was reacted with the bromo THP-ether207a and subsequently hydrolyzed to give hydroxy ester 221. Purificationof 221 from traces of 209c was now easily accomplished by chromatography(60% yield). Subsequent oxidation of this alcohol with pyridiniumdichromate (PDC) in DMF (Vedejs, E. et al. J. Am. Chem. Soc. 1987, 109,5437-5446) afforded diacid monoester 223 (79%), which was furthersaponified to provide 225 in 60% yield after crystallization fromdiethyl ether/hexanes.

The same strategy was applied for the synthesis of the unsymmetricalketodiacid 226. In this case, intermediate 220 was not isolated, butfurther alkylated in situ with bromo THP-ether 207g. After deprotectingthe ketone group by acid treatment and purification of the crude productby chromatography, hydroxy ester 222 was isolated in 36% yield. Inanalogy to its shorter chain homologue 221, oxidation of compound 222with PDC in DMF led to ketodiacid mono-ester 224 (68%). Subsequenthydrolysis of 224 with potassium hydroxide in aqueous ethanol followedby chromatographic purification and crystallization furnished 226 in 43%yield.

Benzophenone derivative 227, prepared similarly to the method describedin Shultz, D. A. et al. The Effect of Phenyl Rin Torsional Rigidity onthe Photophysical Behavior of Tetraphenylethylenes. J. Am. Chem. Soc.1989, 111, 6311-6320, was used as starting material for the synthesis ofaryl-bridged ketones 231 and 232. Bromide displacement in 227 byreaction with lithio ethyl isobutyrate in THF/DMPU at −78° C. producedthe diester 228 in 89% yield. Conversion of 228 to diacid 231 performedby saponification with KOH resulted in practically quantitative yield.For the synthesis of the related diol 232, the ketone moiety inintermediate 228 was first protected as S,S-acetal 229 (87%) asdescribed in Rao, A. V. R. et al. A New Route for the Synthesis of1,4-Dicarbonyl Compounds: Synthesis of Jasmone, Dihydrojasmone and aProstaglandin Intermediate. Synth. Commun. 1984, 14, 469-475. Reductionwith lithium borohydride and methanol gave diol 230 in 85% yield.Finally, deprotection with copper(II) oxide and copper(II) chloride in arefluxing acetone/DMF solvent mixture as described in Stüitz, P. et al.3-Alkylated and 3-Acylated Indoles from a Common Precursor:3-Benzylindole and 3-Benzoylindole. In Organic Syntheses CollectiveVolume VI; Noland, W. E., Editor-in-Chief; John Wiley and Sons, Inc.:New York, 1988; pp 109-114 afforded ketodiol 232 in 71% yield.

Representative Procedure for the Synthesis of Ketodiesters:2,2,12,12-Tetramethyl-7-oxotridecanedioic acid diethyl ester (209c).Under N₂-atmosphere, to a solution of 205c (22.4 g, 89.2 mmol) inanhydrous DMSO (300 mL) was added TosMIC (8.71 g, 44.6 mmol), NaH (60%w/w in mineral oil, 4.28 g, 107.0 mmol), and tetrabutylammonium iodide(3.30 g, 8.9 mmol) under cooling with an ice-bath. After the addition,the reaction mixture was stirred for 23 h at room temperature, thencooled with an ice-bath, and carefully hydrolyzed with water (300 mL).The solution was extracted with CH₂Cl₂ (3×150 mL). The combined organiclayers were washed with water (100 mL) and half-saturated aqueous NaClsolution (100 mL), dried over anhydrous MgSO₄, concentrated in vacuo,and dried in high vacuo to give the crude intermediate 208c (26.2 g) asan oil [¹H NMR (CDCl₃): δ 7.85 (d, 2H, J=8.3), 7.42 (d, 2H, J=8.3), 4.12(q, 4H, J=7.0), 2.49 (s, 3H), 1.94 (m, 4H), 1.60-1.34 (m, 8H), 1.30-1.15(m, 4H), 1.25 (t, 6H, J=7.0), 1.15 (s, 12H). ³C NMR (CDCl₃): δ 177.77,164.08, 146.43, 131.20, 130.34, 129.96, 81.78, 60.37, 42.12, 40.27,33.21, 25.25, 25.19, 24.97, 24.26, 21.86, 14.34]. To a solution of 208c(26.0 g) in CH₂Cl₂ (400 mL) was added concd HCl (100 mL) and thereaction mixture was stirred for 45 min at room temperature. Thesolution was diluted with water (400 mL) and the layers were separated.The aqueous layer was extracted with CH₂Cl₂ (300 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ solution (100mL) and saturated aqueous NaCl solution (100 mL). The organic phaseswere dried over anhydrous MgSO₄, concentrated in vacuo, and dried inhigh vacuo. The residue was purified by flash chromatography (silicagel; hexanes/ethyl acetate=95/5, then 90/10) to give 209c (11.0 g, 67%)as an oil. ¹H NMR (CDCl₃): δ 4.03 (q, 4H, J=7.1), 2.31 (t, 4H, J=7.5),1.45 (m, 8H), 1.20-1.08 (m, 4H), 1.16 (t, 6H, J=7.1), 1.07 (s, 12H). ¹³CNMR (CDCl₃): δ 211.14, 178.05, 60.34, 42.69, 42.20, 40.52, 25.24, 24.71,24.30, 14.35. HRMS (LSIMS, nba): Calcd for C₂₁H₃₉O₅ (MH⁺): 371.2797,found: 371.2763.

2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic acid diethyl ester(209b). According to the procedure described for the synthesis of 209c,205b (25.0 g, 76.4 mmol), tetrabutylammonium iodide (2.78 g, 7.5 mmol)and TosMIC (7.34 g, 37.6 mmol) in anhydrous DMSO (400 mL) and diethylether (150 mL) was reacted with sodium hydride (60% dispersion inmineral oil, 3.80 g, 95.0 mmol) first under cooling with an ice-bath,then at room temperature for 24 h. Hydrolysis and extraction affordedthe intermediate 208b (28.0 g) as a brown oil. A portion of this crudeintermediate (25.0 g) was then treated with concd aqueous HCl (140 mL)in CH₂Cl₂ (500 mL) for 2 h at room temperature. Aqueous workup,extraction, and purification by flash chromatography (silica gel; ethylacetate/hexanes=1/20, 1/10) furnished 209b (9.5 g, 61%) as a lightyellowish oil. ¹H NMR (CDCl₃): δ 7.40-7.10 (m, 10H), 4.20-4.05 (m, 4H),2.38 (m, 4H), 2.05-1.80 (m, 4H), 1.60 (s, 6H), 1.50-1.20 (m, 4H), 1.22(m, 6H). ¹³C NMR (CDCl₃): δ 210.24, 176.06, 143.71, 128.42, 126.72,125.97, 60.83, 50.13, 42.97, 38.91, 22.73, 22.47, 19.09, 14.13. HRMS(LSIMS, nba): Calcd for C₂₉H₃₉O₅ (MH⁺): 467.2797, found: 467.2772.

7-Oxo-2,12-dimethyl-2,12-diphenyltridecanedioic acid diethyl ester(209d). In analogy to the procedure described for the synthesis of 209c,205d (9.59 g, 30.6 mmol) in anhydrous DMSO (50 mL) was reacted withTosMIC (3.02 g, 15.5 mmol), sodium hydride (60% w/w in mineral oil, 1.44g, 36.0 mmol), and tetrabutyl ammonium iodide (1.10 g, 3.0 mmol), firstunder cooling with a water-bath, then for 96 h at room temperature.Hydrolysis and extraction afforded the crude intermediate 208d (30.0 g)as an oil. A solution of this oil (30.0 g) in CH₂Cl₂ (300 mL) and concdaqueous HCl (40 mL) was stirred for 2 h at room temperature. Afterextractive workup and flash chromatography (silica gel; hexanes/ethylacetate=10/1), 209d (5.0 g, 66%) was obtained as a clear oil togetherwith a less pure fraction (1.17 g, 16%). ¹H NMR (CDCl₃): δ 7.40-7.10 (m,10H), 4.11 (q, 4H, J=7.0), 2.34 (t, 4H, J=7.1), 2.10-1.70 (m, 4H),1.6-1.4 (m, 4H), 1.52 (s, 6H), 1.30-1.00 (m, 10H). ¹³C NMR (CDCl₃): δ210.7, 176.0, 143.8, 128.2, 126.5, 125.8, 60.6, 50.0, 42.4, 38.9, 24.3,24.1, 22.6, 14.0. HRMS (LSIMS, nba): Calcd for C₃₁H₄₃O₅ (MH⁺): 495.3110,found: 495.3106. HPLC: 94.8% pure.

2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic acid diethyl ester(209e). In analogy to the procedure described for the synthesis of 209c,205e (21.0 g, 64.2 mmol) was reacted with tetrabutylammonium iodide(2.37 g, 6.4 mmol), TosMIC (6.26 g, 32.1 mmol) and NaH (60% dispersionin mineral oil, 3.24 g, 81.0 mmol) in anhydrous DMSO (320 mL) anddiethyl ether (110 mL) for 24 h at room temperature. After hydrolysisand extraction, the crude intermediate 208e was stirred in CH₂Cl₂ (500mL) and concd HCl (140 mL) for 2 h at room temperature. Extraction andpurification by flash chromatography (silica gel; ethylacetate/hexanes=1/20, 1/9) afforded 209e (9.0 g, 54%) as a lightyellowish oil. ¹H NMR (CDCl₃): δ 7.10 (d, 4H, J=7.9), 7.02 (d, 4H,J=7.9), 4.05 (q, 4H, J=7.0), 2.25 (t, 4H, J=7.3), 2.20 (s, 6H),1.95-1.70 (m, 4H), 1.42 (s, 6H), 1.50-1.05 (m, 8H), 1.08 (t, 6H, J=7.0).¹³C NMR (CDCl₃): δ 211.10, 176.00, 141.00, 135.80, 128.50, 124.51,60.50, 49.50, 42.01, 39.50, 24.28, 24.05, 22.10, 20.50, 13.00. HRMS(LSIMS, nba): Calcd for C₃₃H₄₇O₅ (MH⁺): 523.3423, found: 523.3405.

2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-oxotridecanedioic aciddiethyl ester (209f). Similar to the procedure given for 209c, 205f(14.13 g, 38.3 mmol) was reacted with TosMIC (3.73 g, 19.1 mmol),tetrabutylammonium iodide (1.30 g, 3.5 mmol), and NaH (2.0 g, 60%, 50.0mmol) in freshly distilled DMSO (200 mL) for 18 h at room temperature.The crude intermediate 208f obtained after hydrolysis and extraction wasstirred in CH₂Cl₂ (100 mL) and concentrated HCl (50 mL) for 1 h at roomtemperature. Extractive workup and purification by flash chromatography(silica gel; ethyl acetate/hexanes=10/90, then 20/80) yielded 209f (9.49g, 82%) as a colorless oil. ¹H NMR (CDCl₃): δ 7.18 (d, 4H, J=8.0), 7.07(d, 4H, J=8.0), 4.10 (q, 4H, J=7.0), 2.43 (d, 4H, J=7.0), 2.34 (t, 4H,J=7.6), 2.10-1.92 (m, 2H), 1.92-1.78 (m, 4H), 1.60-1.50(m, 4H), 1.50(s,6H), 1.19-1.11 (m, 5H), 1.17(t, 3H, J=7.0), 0.88(d, 12H, J=6.6). ¹³C NMR(CDCl₃): δ 211.06, 176.39, 141.36, 140.04, 129.16, 125.71, 60.77, 49.90,45.06, 42.66, 39.18, 30.27, 24.59, 24.35, 22.86, 22.56, 14.23. HRMS(LSIMS, nba): Calcd for C₃₉H₅₉O₅ (MH⁺): 607.4362, found: 607.4337.

2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid diethyl ester (209g).According to the procedure described for the synthesis of 209c, asolution of 205g (32.3 g, 115.3 mmol), tetrabutylammonium iodide (3.69g, 10.0 mmol) and TosMIC (9.80 g, 50.2 mmol) in anhydrous DMSO (300 mL)was treated with NaH (4.80 g, 120.0 mmol, 60% in mineral oil) at roomtemperature for 20 h. The intermediary dialkylated TosMIC derivative208g obtained after aqueous workup (36.8 g) was then hydrolyzed withconcd hydrochloric acid (110 mL) in CH₂Cl₂ (450 mL) at room temperaturefor 1 h. Extractive workup and purification by column chromatography(silica gel; hexanes/ethyl acetate=11/1) afforded 209g (12.20 g, 61%) asa colorless oil. ¹H NMR (CDCl₃): δ 4.11 (q, 4H, J=6.9Hz), 2.37 (t, 4H,J=7.5), 1.58-1.47 (m, 8H), 1.35-1.10 (m, 8H), 1.24 (t, 6H, J=7.2), 1.15(s, 12H). ¹³C NMR (CDCl₃): δ 211.6, 178.3, 60.5, 43.1, 42.5, 40.9, 30.1,25.5, 25.1, 24.1, 14.7. HRMS (LSIMS, gly): Calcd for C₂₃H4305 (MH⁺):399.3110, found: 399.3129.

2,2,18,18-Tetramethyl-10-oxononadecanedioic acid diethyl ester (209j).Under N₂ atmosphere, NaH (60% w/w in mineral oil, 1.21 g, 30.2 mmol) wasadded in portions to a solution of TosMIC (2.43 g, 12.5 mmol) andtetrabutylammonium iodide (0.462 g, 1.25 mmol) in dry DMSO (100 mL)while stirring vigorously and cooling with a water bath. After 15 min,205j (7.65 g, 26.1 mmol) was added dropwise in 20 min. After 1 h, H₂O(100 mL) was added dropwise and the resulting mixture was extracted withEt₂O (3×100 mL). The combined organic layers were washed with brine(2×100 mL), dried over anhydrous Na₂SO₄ and evaporated in vacuo. Theresidue was purified by column chromatography (silica, heptane:ethylacetate=6:1) to give 208j (5.41 g) as a yellow oil. To a portion of thisoil (5.03 g), dissolved in CH₂Cl₂ (100 mL), was added aqueous HCl(concd, 30 mL) and the resulting mixture was stirred vigorously for 17.5h. Water (100 mL) was added and the layers were separated. The aqueousphase was extracted with CH₂Cl₂ (100 mL) and the combined organic layerswere washed with NaHCO₃ solution (2×100 mL) and brine (100 mL), driedover anhydrous Na₂SO₄ and evaporated in vacuo. The residue was purifiedby column chromatography (silica, heptane:ethyl acetate=7:1) to give209j (3.21 g, 61%) as a colorless oil. ¹H NMR (CDCl₃): δ (ppm): 4.11 (q,J=7.2, 4H), 2.37 (t, J=7.4, 4H), 1.57-1.46 (m, 8H), 1.28-1.23 (m, 16H),1.24 (t, J=7.1, 6H), 1.15 (s, 12H). ¹³C NMR (CDCl₃): δ (ppm): 211.5,178.0, 60.08, 60.07, 42.7, 42.1, 40.7, 29.9, 29.21, 29.15, 25.1, 24.8,23.8, 14.2. HRMS: Calcd for C₂₇H₅₀O₅ (MH⁺): 454.3658, found: 454.3663.

9-Isocyano-2,2,16,16-tetramethyl-9-(toluene-4-sulfonyl)-heptadecanedioicacid diethyl ester (208i). To a solution of 205i (35.0 g, 125.4 mmol),tetrabutylammonium iodide (4.6 g, 12.5 mmol), and TosMIC (12.2 g, 62.5mmol) in anhydrous DMSO (450 mL) was added NaH (60% dispersion inmineral oil, 6.3 g, 158 mmol) under cooling with an ice-water bath andunder N₂ atmosphere. The reaction mixture was stirred for 23 h atambient temperature, then carefully hydrolyzed with ice-water (500 mL)and extracted with MTBE (3×200 mL). The organic layers were washed withwater (300 mL) and brine (150 mL), dried over anhydrous MgSO₄, andconcentrated in vacuo to give crude 8i (37.0 g, 100%) as an oil. ¹H NMR(CDCl₃): δ (ppm): 7.88 (d, J=7.9, 2H), 7.42 (d, J=7.9, 2H), 4.10 (q,J=7.5, 4H), 2.48 (s, 3H), 2.05-1.75 (m, 3H), 1.65-1.20 (m, 21H), 1.15(t, J=7.5, 6H), 1.10 (s, 12H). ¹³C NMR (CDCl₃): δ (ppm): 177.89, 163.75,146.23, 131.08, 130.28, 129.82, 81.79, 60.17, 42.09, 40.57, 33.09,29.68, 29.31, 25.17, 24.78, 23.66, 21.08, 14.31. HRMS (LSIMS, gly):Calcd for C₃₇H₅₄NO₆S (MH⁺): 592.3672, found: 592.3667.

2,2,16,16-Tetramethyl-9-oxoheptadecanedioic acid diethyl ester (209i).To a solution of 208i (12.0 g, 20.3 mmol) in CH₂Cl₂ (200 mL) was addedconcd HCl (47 mL). The reaction mixture was stirred for 80 min at roomtemperature and diluted with water (200 mL). The layers were separatedand the aqueous layer was extracted with CH₂Cl₂ (3×70 mL). The combinedorganic layers were washed with saturated NaHCO₃ solution (3×40 mL) andbrine (50 mL), dried over anhydrous MgSO₄, and concentrated in vacuo toyield the crude product (7.52 g). Purification by column chromatography(silica gel, ethyl acetate/hexanes=1/9) gave 209i (3.5 g, 40.0%) as acolorless oil. ¹H NMR (CDCl₃): δ (ppm): 4.14 (q, J=7.1, 4H), 2.41 (t,J=7.0, 4H), 1.66-1.45 (m, 8H), 1.35-1.20 (m, 12H), 1.25 (t, J=7.1, 6H),1.17 (s, 12H). ¹³C NMR (CDCl₃): δ (ppm): 211.24, 177.89, 60.01, 42.69,42.07, 40.64, 29.86, 29.07, 25.13, 24.73, 23.74, 14.24. HRMS (LSIMS,gly): Calcd for C₂₅H₄₇O₅ (MH⁺): 427.3423, found: 427.3430.

Representative Procedure for the Saponification of Ketodiesters:2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-oxotridecanedioic acid(210f). A solution of 209f (3.0 g, 4.95 mmol) and KOH (85%, 4.4 g, 66.7mmol) in ethanol (40 mL) and water (10 mL) was heated to reflux for 6 h.The ethanol was removed under reduced pressure and the mixture wasdiluted with water (200 mL). The solution was extracted with Et₂O (100mL) and the aqueous layer was acidified with concentrated HCl (10 mL) topH 1. The product was extracted with Et₂O (2×100 mL). The etherfractions were combined, dried over Na₂SO₄, concentrated and dried inhigh vacuo to yield 210f (2.35 g, 86%) as a light yellow foam. ¹H NMR(CDCl₃): δ 10.02 (br., 2H), 7.24 (d, 4H, J=8.0), 7.09 (d, 4H, J=8.0),2.43 (d, 4H, J=7.0), 2.33 (t, 4H, J=7.3), 2.05-1.88 (m, 2H), 1.96-1.77(m, 4H), 1.55-1.42 (m, 10H), 1.22-1.08 (m, 4H), 0.88 (d, 12H, J=6.6).¹³C NMR (CDCl₃): δ 211.48, 182.94, 140.43, 140.24, 129.27, 125.94,49.71, 45.06, 42.58, 42.58, 38.91, 30.25, 24.45, 24.24, 22.58, 22.40.HRMS (LSIMS, nba): Calcd for C₃₅H₅₀O₅Na (MNa⁺): 573.355, found:573.3459. HPLC: 86.9% pure. Anal. (C₃₅H₅₀O₅) C, H.

2,10-Dimethyl-6-oxo-2,10-diphenylundecanedioic acid (210b). According tothe procedure given for 210f, 209b (14.5 g, 31.1 mmol) was saponifiedwith KOH (85%, 7.2 g, 108.6 mmol) in water (15 mL) and ethanol (45 mL)at reflux for 6 h. After the usual extractive workup, the crude materialwas purified by flash chromatography (silica gel; ethylacetate/hexanes=1/20, 1/10, 1/2) to give 210b (4.0 g, 31%) as a whitesolid. Mp 44-46° C. ¹H NMR (CDCl₃): 10.25 (br., 2H), 7.35-7.22 (m, 10H),2.32 (m, 4H), 1.94-1.86 (m, 4H), 1.57 (s, 6H), 1.51-1.22 (m, 4H). ¹³CNMR (CDCl₃): δ 210.64, 182.66, 142.69, 128.66, 127.18, 126.29, 50.07,42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, gly): Calcd for C₂₅H₃₁O₅ (MH⁺):411.2171, found: 411.2144. HPLC: 95.2% pure.

7-Oxo-2,2,12,12-tetramethyltridecanedioic acid (210c). According to theprocedure given for 210f, 209c (30.0 g, 81.0 mmol) was saponified withKOH (85%, 18.9 g, 286 mmol) in ethanol (143 mL) and water (48 mL) atreflux for 5 h. The solid product obtained after extraction and dryingwas purified by flash chromatography (silica; hexanes/ethylacetate=90/10) to afford 210c (22.0 g, 86%) as a white solid. Mp60-61.5° C. ¹H NMR (CDCl₃): δ 11.40 (br., 2H), 2.41 (t, 4H, J=7.3),1.62-1.48 (m, 8H), 1.32-1.18 (m, 4H), 1.18 (s, 12H). ¹³C NMR (CDCl₃=77.0ppm): δ 211.11, 184.74, 42.49, 42.14, 40.42, 24.92, 24.62, 23.99. HRMS(LSIMS, gly): Calcd for C₁₇H₃₁O₅ (MH⁺): 315.2171, found: 315.2183. HPLC:94.5% pure. Anal. (C₁₇H₃₀O₅) C, H.

2,12-Dimethyl-7-oxo-2,12-diphenyltridecanedioic acid (210d). Accordingto the procedure given for 210f, 209d (3.93 g, 7.9 mmol) was hydrolyzedwith KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL) and water (10 mL) atreflux for 3 h and at room temperature overnight. After the usual workupand drying, 210d (3.0 g, 87%) was obtained as an oil. ¹H NMR (CDCl₃): δ7.40-7.10 (m, 10H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4H), 1.60-1.45(m, 4H), 1.54 (s, 6H), 1.25-1.10 (m, 4H). ¹³C NMR (CDCl₃): δ 211.1,182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3.HRMS (LSIMS, nba): Calcd for C₂₇H₃₅O₅ (MH⁺): 439.2484, found: 439.2497.HPLC: 93.7% pure.

2,12-Dimethyl-7-oxo-2,12-di-p-tolyltridecanedioic acid (210e). Accordingto the procedure given for 210f, 209e (9.0 g, 17.2 mmol) was hydrolyzedwith KOH (85%, 4.0 g, 60.6 mmol) in water (10 mL) and ethanol (30 mL) atreflux for 6 h. After the usual extractive workup, the crude materialwas purified by flash chromatography (silica gel; ethylacetate/hexanes=1/10, 1/6, 1/2) to give 210e (3.1 g, 39%) as a whitesolid. Mp 48-50° C. ¹H NMR (CDCl₃): δ 10.8-8.8 (br., 2H), 7.22 (d, 4H,J=8.1), 7.12 (d, 4H, J=8.1), 2.36 (t, 4H, J=7.5), 2.31 (s, 6H),1.98-1.80 (m, 4H), 1.56-1.44 (m, 4H), 1.51 (s, 6H), 1.24-1.15 (m, 4H).¹³C NMR (CDCl₃): δ 211.63, 183.07, 140.40, 137.00, 129.58, 126.43,50.02, 42.82, 39.10, 24.74, 24.50, 22.82, 21.39. HRMS (LSIMS, gly):Calcd for C₂₉H₃₉O₅ (MH⁺): 467.2797, found: 467.2785. HPLC: 92.4% pure.Anal. (C₂₉H₃₈O₅) C, H.

2,2,14,14-Tetramethyl-8-oxopentadecanedioic acid (210g). According tothe procedure given for 210f, 209g (8.54 g, 21.4 mmol) was saponifiedwith KOH (85%, 4.53 g, 68.6 mmol) in ethanol (13 mL) and water (5 mL) atreflux for 4 h. The solid product obtained after usual workup wasrecrystallized from Et₂O/hexanes (50 mL/50 mL), affording 210g (4.16 g,57%) as colorless needles. Mp 82-83° C. ¹H NMR (CDCl₃): δ 11.53 (br.,2H), 2.39 (t, 4H, J=7.3), 1.60-1.50 (m, 8H), 1.30-1.20 (m, 8H), 1.18 (s,12H). ¹³C NMR (CDCl₃): δ 211.7, 185.0, 42.8, 42.3, 40.4, 29.7, 25.1,24.8, 23.8. HRMS (LSIMS, gly): Calcd for C₁₉H₃₅O₅ (MH⁺): 343.2484,found: 343.2444. HPLC: 92.6% pure. Anal. (C₁₉H₃₄O₅) C, H.

2,2,16,16-Tetramethyl-9-oxoheptadecanedioic acid (210i). To a solutionof KOH (85%, 8.4 g, 127.3 mmol) in deionized water (3.6 mL) and ethanol(11.5 mL) was added 208i (15.0 g, 25.3 mmol) and the mixture was heatedto reflux for 7 h. The reaction mixture was diluted with water (40 mL)and extracted with MTBE (2×30 mL). The aqueous layer was cooled with anice-bath and the pH was adjusted to 1 by addition of 5 N sulfuric acid(45 mL). The aqueous layer was extracted with MTBE (3×30 mL) and thecombined organic layers were washed with brine (50 mL), dried overanhydrous MgSO₄, and concentrated in vacuo to give a crude oil (12.5 g).Purification by chromatography (silica gel, ethyl acetate/hexanes=10% to100%) and recrystallization from MTBE/hexanes (4 mL/50 mL) yielded 210i(5.37 g, 57%) as a white powder. Mp 74.5-76.0° C. ¹H NMR (CDCl₃): δ(ppm): 12.40-11.20 (br, 2H), 2.39 (t, J=7.3, 4H), 1.62-1.48 (m, 8H),1.38-1.22 (m, 12H), 1.11 (s, 12H). ¹³C NMR (CDCl₃=77.02 ppm): δ (ppm):211.88, 184.93, 42.70, 42.19, 40.63, 29.63, 29.09, 24.96, 24.83, 23.83.HRMS (LSIMS, gly): Calcd for C₂₁H₃₉O₅ (MH⁺): 371.2797, found: 371.2804.

2,2,18,18-Tetramethyl-10-oxononadecanedioic acid (210j). To a solutionof 209j (11.63 g, 25.6 mmol) in EtOH and H₂O (3:1, 200 mL) was addedpowdered KOH (85%, 4.31 g, 65.3 mmol). The resulting mixture wasrefluxed for 19 h and concentrated in vacuo until all of the EtOH wasremoved. Water (200 mL) was added and the resulting mixture wasextracted with Et₂O (2×200 mL). The aqueous phase was acidified withaqueous HCl (4 M) to pH˜1 and extracted with Et₂O (3×200 mL). Thecombined Et₂O layers of the latter extraction were dried over anhydrousNa₂SO₄ and evaporated in vacuo. The remaining white solid wasrecrystallized from heptane/iPr₂O to give 210j (7.56 g, 74%) as whitecrystals. Mp 74.3-77.3° C. ¹H NMR (CD₃OD): δ (ppm): 2.43 (t, J=7.3, 4H),1.57-1.50 (m, 8H), 1.33-1.21 (m, 16H), 1.14 (s, 12H). ¹³C NMR (CD₃OD): δ(ppm): 214.5, 182.1, 43.6, 43.2, 42.0, 31.2, 30.4, 30.38, 26.2, 25.9,25.0. HRMS: Calcd for C₂₃H₄₂O₅ (M⁺): 398.3028, found: 398.3032.

2,2,16,16-Tetramethylheptadecane-1,9,17-triol (211i). UnderN₂-atmosphere, methyl tert-butyl ether (MTBE, 80 mL) was added to LiAlH₄(0.67 g, 17.65 mmol) and the suspension was stirred under cooling withan ice-water bath. A solution of 209i (3.0 g, 7.03 mmol) in MTBE (20 mL)was added dropwise, followed by additional MTBE (40 mL). After 2 h at 0°C., the reaction mixture was carefully quenched by addition of ethylacetate (8 mL) and allowed to warm to room temperature overnight. Themixture was cooled with an ice-water bath and carefully hydrolyzed byaddition of crushed ice (15 g) and water (15 mL). The pH was adjusted to1 by addition of 2 N aqueous sulfuric acid (28 mL) and the solution wasstirred at room temperature for 15 min. The layers were separated andthe aqueous layer was extracted with MTBE (40 mL). The combined organiclayers were washed with deionized water (50 mL), saturated NaHCO₃solution (40 mL), and brine (40 mL), dried over anhydrous MgSO₄,concentrated in vacuo and dried in high vacuo. The crude product (2.65g) was purified by recrystallization from hot CH₂Cl₂ (20 mL). Thecrystals were filtered, washed with ice-cold CH₂Cl₂ (20 mL) and dried inhigh vacuo to furnish 211i (1.59 g, 66%) as a white solid. Mp 75-77° C.¹H NMR (CDCl₃): δ (ppm): 3.57 (m, 1H), 3.30 (s, 4H), 1.72 (br, 2H),1.50-1.16 (m, 25H), 0.85 (s, 12H). ¹³C NMR (CDCl₃): δ (ppm): 72.09,38.79, 37.61, 35.21, 30.70, 29.85, 25.78, 24.06, 23.92. HRMS (LSIMS,gly): Calcd for C₂₁H₄₅O₃ (MH⁺): 345.3369, found: 345.3364. HPLC: 95.0%pure.

Representative Procedure for the Dialkylation of TosMIC and Deprotectionto Ketodiols: 1,15-Dihydroxy-2,2,14,14-tetramethylpentadecan-8-one(214g). Under Argon atmosphere, to a solution of 207g (26.0 g, 84.6mmol) and TosMIC (7.8 g, 40.0 mmol) in anhydrous DMSO (200 mL) and THF(10 mL) was added NaH (3.8 g, 95.0 mmol, 60% in mineral oil) in fiveportions at 20-30° C. under cooling with a water bath. After theaddition of tetrabutylammonium iodide (3.0 g, 8.1 mmol), the reactionmixture was stirred at room temperature for 20 h and then hydrolyzedwith water (400 mL). The mixture was extracted with Et₂O (3×100 mL). Thecombined organic layers were washed with saturated aqueous NaCl solution(100 mL), dried over MgSO₄, and concentrated in vacuo to yield the crudedialkylated intermediate (28.2 g) as an orange oil, which was usedwithout purification. To a solution of this crude product (28.0 g) inmethanol (115 mL) was added dilute H₂SO₄ (46 g, 12 mL of concd H₂SO₄ in24 mL of water) over a period of 10 min, and the mixture was stirred for80 min at room temperature. The solution was diluted with water (120 mL)and extracted with CH₂Cl₂ (150 mL, 100 mL, 50 mL). The combined organiclayers were washed with saturated aqueous Na₂CO₃ solution (2×100 mL),saturated aqueous NaHCO₃ solution (100 mL), water (200 mL), andsaturated aqueous NaCl solution (150 mL). The organic extract was driedover anhydrous MgSO₄ and concentrated in vacuo. The residue (18.4 g) waspurified by column chromatography (silica gel; hexanes, then CH₂Cl₂,then hexanes/ethyl acetate=4/3) to give 214g (9.97 g, 79%) as acolorless oil. ¹H NMR (CDCl₃): δ 3.30 (s, 4H), 2.39 (t, 4H, J=7.2), 2.07(br. s, 2H), 1.60-1.55 (m, 4H), 1.28-1.17 (m, 12H), 0.85 (s, 12H). ¹³CNMR (CDCl₃): δ 212.0, 72.0, 43.0, 38.6, 35.2, 30.3, 24.0, 23.8. HRMS(LSIMS, gly): Calcd for C₁₉H₃₉O₃ (MH⁺): 315.2899, found: 315.2886. HPLC:94.7% pure.

1,11-Dihydroxy-2,2,10,10-tetramethylundecan-6-one (214a). In analogy tothe procedure described for the synthesis of 214g, 207a (40.0 g, 143.3mmol) was reacted with TosMIC (13.99 g, 71.7 mmol), tetrabutylammoniumiodide (5.28 g, 14.3 mmol), and NaH (6.86 g, 171.5 mmol) in anhydrousDMSO (400 mL). After extractive workup and drying, the crudeintermediate (47.9 g) was dissolved in methanol (200 mL) and water (40mL) and treated with concd sulfuric acid (20 mL) at room temperature.Workup and purification by chromatography (silica gel; hexanes/ethylacetate=90/10, 70/30, then 50/50) afforded 214a (5.6 g, 30%) as an oil.¹H NMR (CDCl₃): δ 3.30 (s, 4H), 2.68 (br. s, 2H), 2.40 (t, 4H, J=7.2),1.53 (m, 4H), 1.20 (m, 4H), 0.86 (s, 12H). ¹³C NMR (CDCl₃=77.0 ppm): δ212.25, 70.99, 43.15, 37.69, 34.94, 23.89, 17.91. HRMS (LSIMS, gly):Calcd for C₁₅H₂₉O₂ (MH⁺-H₂O): 241.2168, found: 241.2169. HPLC: 96.7%pure.

1,11-Dihydroxy-2,10-dimethyl-2,10-diphenylundecan-6-one (14b). Inanalogy to the procedure given for 214g, to a solution of 207b (25.0 g,73.3 mmol), tetrabutylammonium iodide (3.0 g, 8.2 mmol), and TosMIC(7.23 g, 37.0 mmol) in anhydrous DMSO (350 mL) was added NaH (60%dispersion in mineral oil, 3.73 g, 93.3 mmol) while controlling thetemperature with an ice bath. After the addition of Et₂O (100 mL), themixture was stirred at room temperature for 24 h, hydrolyzed, extracted,and dried to afford the dialkylated TosMIC intermediate (28.0 g) as abrown oil. This crude intermediate was heated to reflux for 3 h inmethanol (500 mL), concd HCl (60 mL), and water (120 mL). Extractiveworkup and purification by flash chromatography (silica gel; hexanes,then ethyl acetate/hexanes=1/20, 1/10, 1/2, 1/1) gave 214b (5.3 g, 38%)as a light yellowish oil. ¹H NMR (CDCl₃): δ (ppm) 7.38-7.30 (m, 8H),7.26-7.18 (m, 2H), 3.62 (d, 2H, J=10.5 Hz), 3.48 (d, 2H, J=10.5 Hz),2.25 (m, 6H), 1.76-1.64 (m, 2H), 1.58-1.16 (m, 6H), 1.32 (s, 6H). ¹³CNMR (CDCl₃): δ (ppm) 211.43, 144.84, 128.32, 126.58, 126.03, 71.79,43.11, 42.89, 37.61, 21.68, 18.12. HRMS (LSIMS, nba): Calcd for C₂₅H₃₃O₂(MH⁺-H₂O): 365.2481, found: 365.2482. HPLC: 89.5% pure.

1,13-Dihydroxy-2,2,12,12-tetramethyltridecan-7-one (214c). Similar tothe procedure given for the synthesis of 214g, 207c (13.0 g, 44.3 mmol)was treated with TosMIC (4.33 g, 22.17 mmol), NaH (60% dispersion inmineral oil, 2.13 g, 53.2 mmol), and tetrabutylammonium iodide (1.64 g,4.4 mmol) in anhydrous DMSO (100 mL) and anhydrous diethyl ether (50 mL)at room temperature overnight. Hydrolysis and extraction afforded thedialkylated TosMIC intermediate (15.5 g) as an oil that was dissolved inmethanol (180 mL), concd HCl (20 mL), and water (40 mL) and heated toreflux for 2 h. Extractive workup and purification by flashchromatography (silica gel; hexanes/ethyl acetate=50/50) furnished 214c(4.3 g, 68%) as a colorless oil. ¹H NMR (CDCl₃): δ 3.28 (s, 4H), 2.80(br. m, 2H), 2.42 (t, 4H, J=7.3), 1.54 (m, 4H), 1.25 (m, 8H), 0.84 (s,12H). ¹³C NMR (CDCl₃): δ 212.06, 71.24, 42.47, 38.11, 34.76, 24.45,23.72, 23.25. HRMS (LSIMS, gly): Calcd for C₁₇H₃₅O₅ (MH⁺): 287.2556,found: 287.2585. HPLC: 97.5% pure.

1,13-Dihydroxy-2,12-dimethyl-2,12-diphenyltridecan-7-one (214d).According to the procedure described for the synthesis of 214g, 207d(10.0 g, 28.2 mmol) was reacted with tetrabutylammonium iodide (1.06 g,2.9 mmol), TosMIC (2.34 g, 12.0 mmol) and NaH (60% dispersion in mineraloil, 1.42 g, 35.5 mmol) in anhydrous DMSO (100 mL) and anhydrous Et₂O(50 ml) at room temperature for 24 h. After aqueous workup andextraction, the dialkylated TosMIC intermediate (11.0 g) was heated toreflux in a mixture of methanol (180 mL), concd HCl (20 mL), and water(40 mL) for 3 h. After extraction, the crude oil was purified by flashchromatography (silica gel; hexanes/ethyl acetate=80/20, then 60/40),affording 214d (3.0 g, 61%) as a colorless oil. ¹H NMR (CDCl₃):7.37-7.28 (m, 8H), 7.24-7.17 (m, 2H), 3.69 (dd, 2H, J=10.9, 5.2), 3.52(dd, 2H, J=10.9, 7.5), 2.26 (t, 4H, J=7.3), 1.75 (m, 2H), 1.61 (s, 2H),1.57-1.40 (m, 6H), 1.33 (s, 6H), 1.29-1.06 (m, 2H), 1.04-0.80 (m, 2H).¹³C NMR (CDCl₃), δ (ppm): 211.21, 144.72, 128.23, 126.50, 125.92, 72.17,43.14, 42.38, 38.06, 24.27, 23.34, 21.42. HRMS (LSIMS): Calcd forC₂₇H₃₉O₃ (MH⁺): 411.2899, found: 411.2899. HPLC: 92.7% pure.

1,13-Dihydroxy-2,12-dimethyl-2,12-di-p-tolyltridecan-7-one (214e).According to the procedure for the synthesis of 214g, 207e (21.5 g, 75.3mmol) was reacted with tetrabutylammonium iodide (2.36 g, 6.4 mmol),TosMIC (5.68 g, 29.1 mmol) and NaH (60% dispersion in mineral oil, 2.94g, 73.5 mmol) in anhydrous DMSO (300 mL) and anhydrous Et₂O (100 mL) atroom temperature for 24 h. The crude intermediate (18.4 g) obtainedafter aqueous workup and extraction was then heated to reflux inmethanol (300 mL), concd HCl (36 mL), and water (70 mL) for 3 h.Extractive workup and purification by flash chromatography (silica gel;hexanes/ethyl acetate=20/1, 15/1, 10/1, 5/1, and 1/1) gave 214e (2.72 g,21%) as a colorless oil. ¹H NMR (CDCl₃): δ 7.18 (d, 4H, J=8.1), 7.12 (d,4H, J=8.1), 3.61 (d, 2H, J=11.0), 3.48 (d, 2H, J=11.0 Hz), 2.31 (s, 6H),2.26 (t, 4H, J=7.8), 1.78-1.40 (m, 10H), 1.29 (s, 6H), 1.24-0.82 (m,4H). ¹³C NMR (CDCl₃): δ 211.51, 141.75, 135.64, 129.23, 126.64, 72.54,43.06, 42.65, 38.28, 24.53, 23.59, 21.66, 20.98. HRMS (LSIMS, gly):Calcd for C₂₉H₄₃O₃ (MH⁺): 439.3212, found: 439.3222. HPLC: 95.4% pure.

1,15-Dihydroxy-2,14-dimethyl-2,14-diphenylpentadecan-8-one (214h). Inanalogy to the procedure of 214g, to a solution of 207h (18.0 g, 63.1mmol), tetrabutylammonium iodide (2.0 g, 5.4 mmol) and TosMIC (4.8 g,24.6 mmol) in anhydrous DMSO (250 mL) and Et₂O (80 mL) was added NaH(60% dispersion in mineral oil, 2.5 g, 62.5 mmol) while cooling with anice bath under N₂ atmosphere. After 24 h at room temperature, themixture was hydrolyzed and worked up by extraction to give the crudeintermediate (18.0 g) as a brown oil. This crude material was heated toreflux in methanol (300 mL), concd HCl (36 mL) and water (70 mL) for 3h. Extractive workup and purification by flash chromatography (silicagel; hexanes/ethyl acetate/hexanes=10/1, 5/1, 2/1) yielded 214h (6.1 g,56%) as a yellowish oil. ¹H NMR (CDCl₃): δ 7.32-7.19 (m, 10H), 3.68 (d,2H, J=10.8), 3.50 (d, 2H, J=10.8), 2.26 (t, 4H, J=7.50H), 1.88-1.42 (m,10H), 1.25 (s, 6H), 1.22-0.85 (m, 8H). ¹³C NMR (CDCl₃): δ 211.68,144.94, 128.56, 126.82, 126.23, 72.68, 43.50, 42.79, 38.42, 30.01,23.74, 23.68, 21.62. HRMS (LSIMS, nba): Calcd for C₂₉H₄₃O₃ (MH⁺):439.3212, found: 439.3207. HPLC: 95.3% pure.

2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tridecanedioicacid diethyl ester (212f). Compound 209f (5.50 g, 9.06 mmol) wasdissolved in CH₂Cl₂ (freshly distilled from CaH₂, 60 mL) with borontrifluoride diethyl etherate (0.45 mL, 0.50 g, 3.55 mmol) and1,3-propanedithiol (1.0 mL, 1.08 g, 9.99 mmol). The solution was stirredfor 3 h at room temperature under a nitrogen atmosphere. An additionalvolume of CH₂Cl₂ (100 mL) was added and the solution was extracted with5% sodium hydroxide solution (2×50 mL) and water (100 mL). After dryingwith anhydrous Na₂SO₄, filtration, and concentration, the product waspurified by flash chromatography (silica gel; ethylacetate/hexanes=10/90), affording 212f (6.16 g, 98%) as a colorless oil.¹H NMR (CDCl₃): δ 7.20 (d, 4H, J=8.0), 7.07 (d, 4H, J=8.0), 4.10 (q, 4H,J=7.0), 2.76 (t, 4H, J=5.3), 2.43 (d, 4H, J=7.0), 2.09-1.95 (m, 2H),1.94-1.78 (m, 10H), 1.51 (s, 6H), 1.46-1.36 (m, 4H), 1.25-1.12 (m, 4H),1.18 (t, 6H, J=7.0), 0.88 (d, 12H, J=6.5). ¹³C NMR (CDCl₃): δ 176.42,141.43, 140.00, 129.14, 125.74, 60.74, 53.30, 49.97, 45.05, 39.22,38.29, 30.26, 26.10, 25.64, 25.17, 24.76, 22.99, 22.56, 14.26. HRMS(EI): Calcd for C₄₂H₆₄O₄S₂ (M⁺): 696.4246, found: 696.4234. HPLC: 96.2%pure.

2,12-Bis-(4-isobutylphenyl)-2,12-dimethyl-7-([1,3]dithianyl)-tridecane-1,13-diol(213f). A solution of 212f (5.81 g, 8.33 mmol) in freshly distilled THF(50 mL) was added dropwise to a suspension of LiAlH₄ (1.0 g, 26.4 mmol)in THF (50 mL) at −78° C. under a nitrogen atmosphere. The solution waswarmed to room temperature over 4 h, then cooled back to −78° C., andquenched with ethyl acetate (5.0 mL). After warming to room temperature,water (100 mL) was added and the product was extracted with Et₂O (2×100mL). The ether extracts were combined, dried with sodium sulfate,filtered, and concentrated. After drying under high vacuum for 4 h, 213f(4.80 g, 94%) was obtained as a colorless oil. ¹H NMR (CDCl₃): δ 7.20(d, 4H, J=8.0), 7.09 (d, 4H, J=8.0), 3.64 (d, 2H, J=10.7), 3.48 (d, 2H,J=10.7), 2.71 (t, 4H, J=5.1), 2.50-2.35 (m br., 2H), 2.43 (d, 4H,J=7.0), 1.90-1.80 (m, 4H), 1.80-1.68 (m, 6H), 1.58-1.42 (m, 2H),1.38-1.25 (m, 4H), 1.30 (s, 6H), 1.26-1.10 (m, 2H), 1.10-0.95 (m, 2H),0.89 (d, 12H, J=6.6). ¹³C NMR (CDCl₃): δ 141.94, 139.39, 129.20, 126.44,72.48, 53.30, 44.97, 43.09, 38.45, 38.18, 30.21, 26.01, 25.64, 24.84,24.09, 22.55, 21.64. HRMS (LSIMS, nba): Calcd for C₃₈H₆₁O₂S₂ (MH⁺):613.4113, found: 613.4075. HPLC: 97.6% pure.

1,13-Dihydroxy-2,12-bis-(4-isobutylphenyl)-2,12-dimethyltridecan-7-one(214f). To a mixture of 213f (4.50 g, 7.34 mmol) in dimethoxyethane (50mL) and concentrated HCl (10 mL) was added dropwise DMSO (5.0 mL) over 5min. The solution was stirred for 30 min at room temperature, thenslowly poured into saturated aqueous NaHCO₃ solution (100 mL) andextracted with Et₂O (2×100 mL). The ether fractions were combined, driedwith anhydrous Na₂SO₄, filtered, and concentrated. The product waspurified by flash chromatography (silica gel; ethylacetate/hexanes=30/70), affording 214f (3.2 g, 83%) as a colorless oil.¹H NMR (CDCl₃): δ 7.19 (d, 4H, J=8.0), 7.09 (d, 4H, J=8.0), 3.63 (d, 2H,J=11.0), 3.49 (d, 2H, J=11.0), 2.43 (d, 4H, J=7.0), 2.26 (t, 4H, J=7.3),1.88-1.66 (m, 4H), 1.52-1.41 (m, 8H), 1.29 (s, 6H), 1.15-1.10 (m, 2H),0.98-0.88 (m, 2H), 0.89 (d, 12H, J=6.6). ³C NMR (CDCl₃): δ 211.47,141.97, 139.51, 129.28, 126.45, 72.53, 45.02, 43.11, 42.69, 38.36,30.26, 24.57, 23.63, 22.58, 21.72. HRMS (LSIMS, nba): Calcd for C₃₅H₅₅O₃(MH⁺): 523.4151, found: 523.4144. HPLC: 96.3% pure.

1,17-Dihydroxy-2,2,16,16-tetramethylheptadecan-9-one (214i). To asolution of 211i (2.42 g, 7.02 mmol) in acetic acid (10 mL) was addeddropwise sodium hypochlorite solution (1.76 mL, ca. 3.5 mmol) at 18° C.Additional sodium hypochlorite solution (3×1.0 mL, ca. 6.0 mmol) wasadded after 20, 40, and 60 min under monitoring by TLC. The reaction wasquenched with 2-propanol (4 mL) and diluted with deionized water (100mL). The reaction mixture was extracted with ethyl acetate (3×60 mL).The combined organic layers were washed with saturated NaHCO₃ solution(3×60 mL), water (60 mL) and brine (60 mL), dried over anhydrous MgSO₄,and concentrated in vacuo. Purification of the crude product (2.38 g) bycolumn chromatography (silica gel, ethyl acetate/hexanes=1/1) gave 214i(0.83 g, 35%) as a colorless wax. ¹H NMR (CDCl₃): δ (ppm): 3.33 (s, 4H),2.41 (t, J=7.4, 4H), 1.85 (br, 2H), 1.62-1.45 (m, 4H), 1.35-1.18 (m,16H), 0.87 (s, 12H). ¹³C NMR (CDCl₃): δ (ppm): 212.09, 72.10, 42.99,38.75, 35.20, 30.48, 29.42, 24.05, 23.99, 23.82. HRMS (LSIMS, gly):Calcd for C₂₁H₄₃O₃ (MH⁺): 343.3212, found: 343.3208. HPLC: 96.4% pure.

2-[7-Isocyano-2,2-dimethyl-7-(toluene-4-sulfonyl)-heptyloxy]-tetrahydropyran(215). Method A. To a solution of TosMIC (9.75 g, 49.9 mmol) andtetrabutylammonium iodide (1.69 g, 4.6 mmol) in anhydrous DMSO (240 mL)was added NaH (2.2 g, 55.0 mmol, 60% in mineral oil), while cooling withan ice bath. 207c (14.65 g, 50 mmol) was added dropwise over 1 h and thereaction mixture was stirred at room temperature overnight. The mixturewas quenched with water (100 mL) and extracted with CH₂Cl₂ (3×100 mL).The combined organic layers were washed with water (100 mL) andhalf-saturated aqueous NaCl solution (100 mL), dried over anhydrousNa₂SO₄, and concentrated in vacuo to afford the crude product (30 g),which was purified by column chromatography (silica gel; hexanes/ethylacetate=90/10) to obtain 215 (5.4 g, 27%) as a colorless oil. ¹H NMR(CDCl₃): δ 7.87 (d, 2H, J=8.2), 7.43 (d, 2H, J=8.2), 4.56-4.40 (m, 2H),3.83 (t, 1H, J=8.1), 3.58-3.38 (m, 1H), 3.46 (d, 1H, J=9.2), 2.97 (d,1H, J=9.2), 2.49 (s, 3H), 2.30-1.20 (m, 16H), 0.88 (s, 6H). ¹³C NMR(CDCl₃): δ 164.7, 146.5, 131.1, 130.1, 99.1, 76.2, 62.0, 38.7, 34.1,30.6, 28.3, 26.2, 25.5, 24.5, 23.0, 21.8, 19.5. HRMS (LSIMS, nba): Calcdfor C₂₂H₃₄NSO₄ (MH⁺): 408.2209, found: 408.2205.

Method B. To a solution of TosMIC (3.9 g, 20.0 mmol) in anhydrous DMF(100 mL) was added K₂CO₃ (5.52 g, 39.9 mmol), 207c (11.72 g, 40.0 mmol),and tetrabutylammonium iodide (0.74 g, 1.95 mmol). The reaction mixturewas stirred at room temperature for 20 h and then heated to 50° C. for 4h. The reaction mixture was poured into ice water (300 mL) and extractedwith CH₂Cl₂ (3×60 mL). The combined organic layers were washed withwater (2×100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuoto afford the crude product, which was purified by column chromatography(silica gel; hexanes/ethyl acetate=90/10) to give 215 (5.6 g, 69%) as acolorless oil.

1,12-Dihydroxy-2,2,11,11-tetramethyldodecan-6-one (217). To a solutionof 215 (6.5 g, 15.9 mmol) in anhydrous DMSO (70 mL) was added NaH (0.77g, 19.3 mmol, 60% in mineral oil), 207a (4.91 g, 17.6 mmol), andtetrabutylammonium iodide (0.59 g, 1.6 mmol). The reaction mixture wasstirred at room temperature for 24 h and hydrolyzed with water (100 mL).The product was extracted with CH₂Cl₂ (3×100 mL). The combined organiclayers were washed with water (3×100 mL), dried over anhydrous Na₂SO₄and concentrated in vacuo to give the crude intermediate (14.0 g). Thiscrude material was heated to reflux in concentrated HCl (17 mL) andmethanol (100 mL) overnight. The reaction mixture was poured into icewater (200 mL) and extracted with Et₂O (3×100 mL). The combined organiclayers were washed with 5% NaOH solution (60 mL) and water (2×100 mL),dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby column chromatography (silica gel; hexanes/ethyl acetate=80/20),affording 217 (2.5 g, 58%) as a colorless oil. ¹H NMR (CDCl₃): δ 3.31(s, 2H), 3.28 (s, 2H), 2.42-2.37 (m, 4H), 2.4-1.8 (m br., 2H), 1.56-1.48(m, 4H), 1.22-1.14 (m, 6H), 0.85 (s, 6H), 0.84 (s, 6H). ¹³C NMR (CDCl₃):δ 212.0, 71.5, 71.1, 43.0, 42.7, 38.2, 37.7, 35.0, 34.9, 30.8, 24.6,23.9, 23.8, 23.4, 17.8. HRMS (LSIMS, gly): Calcd for C₁₆H₃₃O₃ (MH⁺):273.2430, found: 273.2422. HPLC: 91.4% pure.

1,13-Dihydroxy-2,2,12-trimethyl-12-phenyltridecan-7-one (218). To asolution of 215 (5.3 g, 13.0 mmol) in anhydrous DMSO (60 mL) was addedNaH (0.62 g, 15.5 mmol, 60% in mineral oil), 207d (4.6 g, 12.9 mmol),and tetrabutylammonium iodide (0.48 g, 1.3 mmol). The reaction mixturewas stirred at room temperature overnight and hydrolyzed with water (100mL). The product was extracted with CH₂Cl₂ (3×100 mL) and the combinedorganic phases were washed with water (100 mL) and half-saturatedaqueous NaCl solution (100 mL), dried over sodium sulfate andconcentrated in vacuo to get the crude intermediate (9.0 g). This crudematerial was heated to reflux in concentrated HCl (13.4 mL) and methanol(60 mL) overnight. The reaction mixture was poured into water (200 mL)and the product was extracted with Et₂O (3×60 mL). The combined organiclayers were washed with water (3×20 ml), dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatography(silica gel; hexanes/ethyl acetate=2/1), affording 218 (3.2 g, 71%) as acolorless oil. ¹H NMR (CDCl₃): δ 7.38-7.16 (m, 5H), 3.67 (d, 1H,J=10.9), 3.52 (d, 1H, J=10.9), 3.26 (s, 2H), 2.40-2.20 (m, 4H),1.85-1.60 (m, 3H), 1.60-1.40 (m, 5H), 1.33 (s, 3H), 1.28-1.10 (m, 5H),1.10-0.90 (m, 1H), 0.83 (s, 6H). ¹³C NMR (CDCl₃=77.0 ppm): δ 211.5,144.6, 128.3, 126.6, 126.0, 72.3, 71.6, 43.3, 42.5, 38.2, 34.9, 24.6,24.4, 23.8, 23.4, 21.5. HRMS (LSIMS, gly): Calcd for C₂₂H₃₇O₃ (MH⁺):349.2743, found: 349.2731. HPLC: Alltima C-8 column, 250×4.6 mm, 5μ; 50%acetonitrile/50% water, flow rate 1.0 mL/min; RI, retention time 12.87min, 84.9% pure.

1,14-Dihydroxy-2,2,13,13-tetramethyltetradecan-7-one (219). According tothe procedure described for the synthesis of 217, 215 (6.98 g, 17.1mmol) was reacted with NaH (0.82 g, 20.5 mmol, 60% in mineral oil), 207g(5.8 g, 18.9 mmol), and tetrabutylammonium iodide (0.63 g, 1.7 mmol) inanhydrous DMSO (100 mL) for 24 h at room temperature. The crudeintermediate (10.9 g) obtained after aqueous workup was heated to refluxin concentrated HCl (18 mL) and methanol (100 mL) overnight. Afterextraction and column chromatography (silica gel; hexanes/ethylacetate=80/20), 219 (2.3 g, 48%) was obtained as a colorless oil. ¹H NMR(CDCl₃): δ 3.30 (s, 4H), 2.48-2.34 (m, 4H), 1.85 (br., 2H), 1.66-1.46(m, 4H), 1.24-1.14 (m, 10H), 0.85 (s, 12H). ¹³C NMR (CDCl₃): δ 211.8,71.8, 71.6, 42.7, 42.6, 38.4, 38.2, 34.9, 30.1, 24.6, 23.8, 23.8, 23.7,23.6, 23.4. HRMS (LSIMS, gly): Calcd for C₁₈H₃₇O₃ (MH⁺): 301.2743,found: 301.2745. HPLC: 97.4% pure.

7-Isocyano-2,2-dimethyl-7-(toluene-4-sulfonyl)-heptanoic acid ethylester (220). Under nitrogen atmosphere, to a stirred solution oftetrabutylammonium iodide (4.23 g, 11.5 mmol) and TosMIC (27.56 g, 141.2mmol) in anhydrous DMSO (500 mL) was added NaH (60% w/w in mineral oil,5.80 g, 145.0 mmol), while keeping the internal temperature between 10and 15° C. After the dropwise addition of 205c (36.60 g, 145.7 mmol),the mixture was stirred at room temperature for 20 h, then cooled withan ice-bath and carefully hydrolyzed with water (600 mL). The solutionwas extracted with CH₂Cl₂ (4×150 mL). The combined organic layers werewashed with water (200 mL) and half-saturated aqueous NaCl solution (200mL), dried over anhydrous MgSO₄, and concentrated in vacuo to obtain thecrude product mixture (40.9 g) as an orange oil. A portion of this crudeproduct (13.0 g) was purified by column chromatography (silica gel;hexanes/ethyl acetate=10/1, then 9/1), affording 220 (1.92 g, 12%) as apale yellow oil, 208c (0.70 g, 3%) as a colorless oil, and a mixture ofboth (2.50 g, ratio 9/1). ¹H NMR (CDCl₃): δ 7.86 (d, 2H, J=8.1), 7.43(d, 2H, J=8.1), 4.48 (dd, 1H, J=7.2, 3.6), 4.11 (q, 2H, J=7.2), 2.49 (s,3H), 2.21-2.16 (m, 1H), 1.90-1.78 (m, 1H), 1.56-1.50 (m, 4H), 1.35-1.20(m, 2H), 1.25 (t, 3H, J=7.2), 1.16 (s, 6H). ¹³C NMR (CDCl₃): δ 177.8,165.0, 146.7, 131.3, 130.3, 130.2, 72.9, 60.5, 42.2, 40.2, 28.3, 25.8,25.3, 25.2, 24.2, 21.9, 14.4. HRMS (LSIMS, nba): Calcd for C₁₉H₂₈NO₄S(MH⁺): 366.1739, found: 366.1746.

Ethyl 12-hydroxy-2,2,11,11-tetramethyl-7-oxo-dodecanoate (221). Undernitrogen atmosphere, to a solution of 220 (1.72 g, 4.68 mmol),tetrabutylammonium iodide (0.17g, 0.46 mmol) and 207a (1.45 g, 5.19mmol) in anhydrous DMSO (20 mL) was added NaH (60% w/w in mineral oil,0.19 g, 4.75 mmol), while keeping the internal temperature between 10and 15° C. The reaction mixture was stirred for 20 h at room temperatureand then carefully hydrolyzed with ice-water (100 mL). The mixture wasextracted with CH₂Cl₂ (3×15 mL). The combined organic layers were washedwith water (40 mL) and saturated aqueous NaCl solution (2×20 mL), driedover anhydrous MgSO₄, and concentrated in vacuo to obtain the crudeintermediate (3.50 g) as brown oil. A solution of this intermediate in48% H₂SO₄ (6 mL) and methanol (12 mL) was stirred for 100 min at roomtemperature. The mixture was diluted with water (50 mL) and extractedwith CH₂Cl₂ (3×15 mL). The combined organic layers were washed withwater (100 mL) and saturated aqueous NaCl solution (100 mL), dried overanhydrous MgSO₄, and concentrated in vacuo to obtain the crude product(2.70 g) as yellow oil. A portion of the crude product (2.50 g) wassubjected to column chromatography (silica gel; hexanes/ethylacetate=80/20, then 75/25) to give 221 (0.82 g, 60%) as a pale yellowoil. ¹H NMR (CDCl₃): δ 4.14-4.03 (m, 2H), 3.31 (br. s, 2H), 2.42 (br.,1H), 2.39 (m, 4H), 1.54-1.48 (m, 6H), 1.24-1.18 (m, 7H), 1.14 (s, 6H),0.86 (s, 6H). ¹³C NMR (CDCl₃): δ 211.7, 178.0, 71.2, 60.3, 43.2, 42.7,42.1, 40.4, 37.9, 35.1, 25.2, 24.6, 24.2, 24.1, 18.0, 14.3. HRMS (LSIMS,gly): Calcd for C₁₈H₃₅O₄ (MH⁺): 315.2535, found: 315.2541.

Ethyl 14-Hydroxy-2,2,13,13-tetramethyl-7-oxotetradecanoate (222).According to the procedure for the synthesis of 220, 205c (45.6 g, 182mmol) was reacted with TosMIC (35.2 g, 180 mmol), tetrabutylammoniumiodide (4.3 g, 11.6 mmol) and NaH (60% w/w in mineral oil, 7.3 g, 183mmol) in anhydrous DMSO (500 mL). To this solution was addedtetrabutylammonium iodide (4.3 g, 11.6 mmol) and 207g (43.8 g, 143 mmol)in anhydrous DMSO (20 mL), and then NaH (7.4 g, 185 mmol, 60% w/w inmineral oil) at 10° C. The reaction mixture was stirred at roomtemperature for 20 h, cooled with an ice-bath, and carefully hydrolyzedwith ice-water (1000 mL). The product was extracted with CH₂Cl₂ (5×100mL). The combined organic layers were dried over anhydrous MgSO₄ andconcentrated in vacuo to obtain the crude intermediate (115 g) as a redoil. This intermediate was dissolved in 48% H₂SO₄ (147 mL) and methanol(480 mL) and the mixture was stirred for 100 min at room temperature.After dilution with water (1500 mL), the product was extracted withCH₂Cl₂ (2×150 mL, 100 mL, 50 mL). The combined organic layers werewashed with saturated aqueous sodium carbonate solution (150 mL) andsaturated aqueous NaCl solution (150 mL), dried over MgSO₄, filteredthrough a short column (aluminum oxide; ethyl acetate), and concentratedin vacuo to obtain the crude product (89 g) as a yellow oil. The crudeproduct was subjected to column chromatography (silica gel;hexanes/ethyl acetate=6:1, then 3:1) to give 222 (17.6 g, 36%) as a paleyellow oil. ¹H NMR (CDCl₃): δ 4.10 (q, 2H, J=6.9), 3.30 (br. s, 2H),2.39 (t, 4H, J=6.9), 1.98 (br., 1H), 1.56-1.48 (m, 6H), 1.27-1.18 (m,11H), 1.14 (s, 6H), 0.85 (s, 6H). ¹³C NMR (CDCl₃): δ 211.5, 178.0, 71.9,60.3, 42.9, 42.7, 42.2, 40.5, 38.6, 35.1, 30.3, 25.2, 24.7, 24.2, 24.0,23.8, 14.4. HRMS (LSIMS, gly): Calcd for C₂₀H₃₉O₄ (MH⁺): 343.2848,found: 343.2846.

2,2,11,11-Tetramethyl-7-oxododecanedioic acid 1-ethyl ester (223). Amixture of 221 (3.26 g, 10.4 mmol) and pyridinium dichromate (14.0 g,37.2 mmol) in DMF (45 mL) was stirred at room temperature for 46 h. Thesolution was diluted with 48% H₂SO₄ (30 mL) and water (300 mL) andextracted with ethyl acetate (5×100 mL). The combined organic layerswere washed with saturated aqueous NaCl solution (5×100 mL), dried overanhydrous MgSO₄, and concentrated in vacuo to give the crude product(3.19 g) as greenish oil. The crude product was subjected to columnchromatography (silica gel; hexanes/ethyl acetate=3:1, 2:1), affording223 (2.69 g, 79%) as a pale yellow oil. ¹H NMR (CDCl₃): δ 11.30 (br.,1H), 4.10 (q, 2H, J=7.2), 2.39 (t, 4H, J=7.2), 1.56-1.48 (m, 8H),1.25-1.15 (m, 2H), 1.24 (t, 3H, J=7.2), 1.20 (s, 6H), 1.15 (s, 6H). ¹³CNMR (CDCl₃): δ 210.9, 184.4, 178.1, 60.4, 43.1, 42.7, 42.2, 40.5, 39.8,25.3, 25.0, 24.7, 24.3, 19.3, 14.4. HRMS (LSIMS, gly): Calcd forC₁₈H₃₃O₅ (MH⁺): 329.2328, found: 329.2330.

2,2,13,13-Tetramethyl-7-oxotetradecanedioc acid 1-ethyl ester (224). Amixture of 222 (10.53 g, 30.7 mmol) and pyridinium dichromate (32.5 g,86.4 mmol) in DMF (120 mL) was stirred at 30° C. for 40 h. The mixturewas poured into 48% sulfuric acid (50 mL) and water (700 mL). Theproduct was extracted with ethyl acetate (3×200 mL, 2×100 mL). Thecombined organic layers were washed with saturated aqueous NaCl solution(4×100 mL), dried over anhydrous MgSO₄, and concentrated in vacuo togive the crude product (10.3 g) as a pale yellow oil. This crudematerial was purified by column chromatography (silica gel;hexanes/ethyl acetate=75/25) to afford 224 (7.40 g, 68%) as a yellowishoil. ¹H NMR (CDCl₃): δ 4.10 (q, 2H, J=7.5), 2.39 (m, 4H), 1.56-1.49 (m,8H), 1.26-1.21 (m, 10H), 1.18 (s, 6H), 1.15 (s, 6H). ¹³C NMR (CDCl₃): δ211.4, 184.2, 178.0, 60.3, 42.8, 42.7, 42.1, 40.5, 40.4, 29.7, 25.2,24.8, 24.7, 24.3, 23.7, 14.3. HRMS (LSIMS, gly): Calcd for C₂₀H₃₇O₅(MH⁺): 357.2641, found: 357.2641.

2,2,11,11-Tetramethyl-6-oxododecanedioc acid (225). According to theprocedure given for 209f, 223 (2.50 g, 7.6 mmol) was saponified with KOH(1.80 g, 27.3 mmol) in water (3 mL) and ethanol (8 mL) at reflux for 4h. After the usual workup, the crude product (2.17 g) was recrystallizedfrom Et₂O/hexanes (15 mL/25 mL) to give 225 (1.36 g, 60%) as whiteneedles. Mp 72-73° C. ¹H NMR (CDCl₃): δ 12.0-11.2 (br., 2H), 2.41 (m,4H), 1.60-1.52 (m, 8H), 1.29-1.24 (m, 2H), 1.20 (s, 6H), 1.18 (s, 6H).¹³C NMR (CDCl₃): δ 211.2, 185.1, 184.9, 43.9, 42.7, 42.2, 40.3, 39.8,25.1, 25.0, 24.7, 24.2, 19.3. HRMS (LSIMS, gly): Calcd for C₁₆H₂₉O₅(MH⁺): 301.2015, found: 301.2023. HPLC: 95.8% pure.

2,2,13,13-Tetramethyl-7-oxotetradecanedioc acid (226). According to theprocedure for the synthesis of 209f, a solution of 224 (7.4 g, 20.8mmol) and KOH (85%, 4.6 g, 69.6 mmol) in water (5 mL) and ethanol (15mL) was heated to reflux for 4 h. The crude product (6.8 g) obtainedafter the usual workup was purified by repeated column chromatography(silica gel; first: hexanes/ethyl acetate=2/1, then 1/1. Second:hexanes/ethyl acetate=1/) and crystallization (Et₂O/hexanes, 20 mL/10mL), affording 226 (2.95 g, 43%) as colorless needles. Mp 61-62° C. ¹HNMR (CDCl₃): δ 11.91 (br., 2H), 2.41 (t, 4H, J=6.9), 2.39 (t, 4H,J=6.9), 1.58-1.52 (m, 8H), 1.30-1.22 (m, 6H), 1.18 (s, 12H). ¹³C NMR(CDCl₃): δ 211.8, 184.5, 185.4, 43.0, 42.9, 42.5, 40.7, 40.6, 29.9,25.4, 25.1, 25.0, 24.6, 23.9. HRMS (LSIMS, gly): Calcd for C₁₈H₃₃O₅(MH⁺): 329.2328, found: 329.2324. HPLC: 93.5% pure.

3-{3-[3-Ethoxycarbonyl-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethylpropionicacid ethyl ester (228). Under inert gas atmosphere and at −78° C., to astirred solution of ethyl isobutyrate (9.78 g, 84.2 mmol) in anhydrousTHF (30 mL) was added dropwise a solution of lithium diisopropylamide(2.0 M, 42.2 mL, 84.4 mmol). After 1 h, 227 (10.34 g, 28.1 mmol) wasadded, followed by addition of N,N′-dimethylpropyleneurea (DMPU, 2.7 g,21.1 mmol). The mixture was stirred for 30 min and then allowed to warmto room temperature over 30 min. The THF was distilled off under reducedpressure. The residue was dissolved in saturated aqueous NH₄Cl solution(280 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with saturated aqueous NaCl solution (200mL), 5% HCl (100 mL) and saturated aqueous NaHCO₃ solution (50 mL).Drying over anhydrous Na₂SO₄ and concentration in vacuo afforded 228(11.0 g, 89%) as an oil. ¹H NMR (CDCl₃): δ 7.8-7.2 (m, 8H), 3.98 (q, 4H,J=6.9), 2.83 (s, 4H), 1.2-0.8 (m, 18H). ¹³C NMR (CDCl₃=77.0 ppm): δ196.5, 176.8, 138.1, 137.2, 134.0, 131.4, 128.1, 127.7, 60.3, 45.7,43.3, 24.8, 13.9.

3-(3-{2-[3-(2-Ethoxycarbonyl-2-methylpropyl}-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethylpropionicacid ethyl ester (229). To a solution of 228 (6.2 g, 14.1 mmol) and1,3-propanedithiol (1.9 g, 17.6 mmol) in CH₂Cl₂ (100 mL) was added borontrifluoride diethyl etherate (0.52 mL, 0.58 g, 4.1 mmol). The solutionwas stirred at room temperature overnight. After the addition of 5% NaOHsolution (17.5 mL), the organic layer was separated, washed with water(50 mL), dried over anhydrous Na₂SO₄, and evaporated to afford 229 (6.5g, 87%) as an oil. ¹H NMR (CDCl₃): δ 7.58-6.96 (m, 8H), 4.10 (q, 4H,J=7.2), 2.85 (s, 4H), 2.76 (t, 4H, J=5.6), 1.98 (m, 2H), 1.22 (t, 6H,J=7.2) 1.13 (s, 12H). ¹³C NMR (CDCl₃=77.0 ppm): δ 177.17, 142.18,138.07, 131.12, 129.30, 127.84, 127.33, 60.35, 46.16, 43.48, 29.38,24.90, 14.13.

3-(3-{2-[3-(3-Hydroxy-2,2-dimethylpropyl)-phenyl]-[1,3]dithian-2-yl}-phenyl)-2,2-dimethylpropan-1-ol(230). To a suspension of LiBH₄ (0.78 g, 35.8 mmol) in CH₂Cl₂ (55 mL)was added methanol (1.04 g, 32.5 mmol) at room temperature. After theaddition of 229 (6.5 g, 12.3 mmol), the reaction mixture was heated toreflux for 6 h. After cooling to room temperature, saturated aqueousNH₄Cl solution (20 mL) and CH₂Cl₂ (15 mL) were added and the layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (2×10 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford 230 (4.66 g, 85%) as an oil. ¹H NMR(CDCl₃): δ 7.42 (s br., 2H), 7.17 (m, 4H), 6.97 (m, 2H), 3.63 (s, 4H),3.16 (s, 4H), 2.69 (m, 2H), 2.47 (m, 4H), 1.88 (m, 2H), 0.75 (s, 12H).¹³C NMR (CDCl₃): δ 142.39, 139.18, 131.69, 129.88, 128.05, 127.01,71.12, 44.89, 43.74, 36.70, 29.63, 24.22.

3-{3-[3-(2-Carboxy-2-methylpropyl)-benzoyl]-phenyl}-2,2-dimethylpropionicacid (231). According to the procedure for the synthesis of 209f, amixture of 228 (4.38 g, 10.0 mmol) and KOH (85%, 1.57 g, 23.8 mmol) washeated to reflux in water (1.5 mL) and ethanol (5 mL) for 3 h. Afterextraction and drying in high vacuo, 231 (3.88 g, quantitative) wasobtained as a white solid. Mp 46-48° C. ¹H NMR (CDCl₃): δ 11.2-10.6(br., 2H), 7.8-7.2 (m, 8H), 2.83(s, 4H), 1.25(s, 12H). ¹³C NMR (CDCl₃):δ 198.02, 183.86, 138.61, 137.73, 134.56, 130.54, 128.41, 128.10, 46.69,43.77, 24.83. HRMS (LSIMS, nba): Calcd for C₂₃H₂₇O₅ (MH⁺): 383.1858,found: 383.1858. HPLC: 88.3% pure.

Bis[3-(3-hydroxy-2,2-dimethylpropyl)-phenyl]-methanone (232). Asuspension of copper(II) oxide (0.96 g, 12.1 mmol) and anhydrouscopper(II) chloride (3.2 g, 23.8 mmol) in acetone (80 mL) was heated toreflux. A solution of 230 (4.44 g, 10.0 mmol) in acetone (20 mL) and DMF(1.2 mL) was added dropwise over 5 min. After 90 min at refluxtemperature, the reaction mixture was cooled to room temperature andfiltered. The insoluble material was washed with CH₂Cl₂ (3×20 mL). Thecombined organic solutions were washed with aqueous 2 N Na₂CO₃ solution(50 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by column chromatography (silica gel;hexanes/acetone=80/20) to give 232 (2.5 g, 71%) as an oil. ¹H NMR(CDCl₃): δ 7.68-7.30 (m, 8H), 3.31 (s, 4H), 3.03 (s br., 2H), 2.65 (s,4H), 0.88 (s, 12H). ¹³C NMR (CDCl₃=77.00 ppm): δ 197.42, 139.06, 136.96,134.60, 131.88, 127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS (LSIMS,nba): Calcd for C₂₃H₃₁O₃ (MH⁺): 355.2273, found: 355.2263. HPLC: 94.5%pure.

Syntheses of Intermediates

2-Phenylpropionic acid ethyl ester (202). Under N₂ atmosphere, asolution of ethyl phenylacetate (800.0 g, 4.87 mol) in anhydrous THF(6.4 L) was cooled to −40° C. and a solution of LDA (2.0 M inheptane/THF, ethylbenzene, 2.43 L, 4.86 mol) was added dropwise over 30min. The reaction mixture was stirred for 1 h, and methyl iodide (968 g,6.82 mol) was added dropwise over 20 min, followed by the addition ofDMPU (320 mL). After 1 h, the reaction mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was pouredinto water (6.4 L) and extracted with ethyl acetate (3×1.6 L). Thecombined organic layers were washed with saturated aqueous NH₄Clsolution (1.6 L), 1 N HCl (1.6 L), saturated aqueous NaHCO₃ solution(1.6 L), and saturated aqueous NaCl solution (1.6 L). The solution wasdried over MgSO₄ and concentrated in vacuo. The residue was distilled inhigh vacuo to give 202 (620.0 g, 72%) as a colorless oil. Bp 55-60°C./0.2 Torr (lit. (Shiner, V. J. et al. J. Am. Chem. Soc. 1961, 83,593-598) bp 59-60° C./0.3 Torr). ¹H NMR (CDCl₃): δ 7.36-7.18 (m, 5H),4.11 (m, 2H), 3.69 (q, 1H, J=7.1), 1.49 (d, 3H, J=7.1), 1.19 (t, 3H,J=7.1). ¹³C NMR (CDCl₃): δ 174.44, 140.73, 128.57, 127.48, 127.04,60.66, 45.59, 18.66, 14.16.

Ethyl 2-p-Tolylpropionate (203). According to the procedure given forthe synthesis of 202, ethyl p-tolylacetate (2.72 g, 15.2 mmol) wasreacted with LDA (7.6 mL, 15.25 mmol) and methyl iodide (3.03 g, 21.30mmol) in anhydrous THF (70 mL) and DMPU (1 mL). After aqueous workup andextraction, the residue was distilled in high vacuo to give 203 (2.5 g,86.0%) as an oil. Bp 59-63° C./0.2 mmHg. ¹H NMR (CDCl₃): δ (ppm) 7.18(d, 2H, J=8.1), 7.10 (d, 2H, J=8.1), 4.09 (m, 2H), 3.67 (q, 1H, J=7.2),2.29 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.20 (t, J=5.7 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃/TMS): δ (ppm) 174.71, 137.80, 136.63, 129.33, 129.14,127.36, 60.66, 45.18, 21.05, 18.70, 14.15.

2-(4-Isobutylphenyl)-propionic acid ethyl ester (204). A solution of2-(4-isobutylphenyl)-propionoic acid (Ibuprofen, 9.6 g, 46.5 mmol) andp-toluenesulfonic acid monohydrate (1.52 g, 7.9 mmol) in benzene (100mL) and ethanol (75 mL) was heated to reflux using a Dean-Starkapparatus for 4 h. The solvent was removed under reduced pressure andthe residue was taken up in Et₂O (100 mL). The solution was extractedwith saturated aqueous NaHCO₃ solution (2×100 mL) and water (2×100 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated, affording 204 (10.44 g, 96%) as a clear oil. ¹H NMR(CDCl₃): δ 7.19 (d, 2H, J=8.0), 7.08 (d, 2H, J=8.0), 4.10 (m, 2H), 3.66(q, 1H, J=7.0), 2.44 (d, 2H, J=7.0), 1.84 (m, 1H), 1.47 (d, 3H, J=7.0),1.19 (t, 3H, J=7.3), 0.89 (d, 6H, J=7.0). ¹³C NMR (CDCl₃): δ 174.92,140.59, 138.07, 129.45, 127.29, 60.79, 45.32, 45.21, 30.35, 22.55,18.78, 14.29. HRMS (LSIMS, nba): Calcd for C₁₅H₂₃O₂ (MH⁺): 235.1698,found: 235.1688.

Ethyl 5-Bromo-2,2-dimethylpentanoate (205a). Described in lit.(Kuwahara, M. et al. Chem. Pharm. Bull. 1997, 45, 1447-1457) Bp65.0-66.5° C./0.4 mmHg (lit. 71-73° C./0.25 mmHg). ¹H NMR (CDCl₃): 4.12(q, 2H, J=7.1), 3.38 (t, 2H, J=6.4), 1.88-1.75 (m, 2H), 1.69-1.61 (m,2H), 1.25 (t, 3H, J=7.1), 1.18 (s, 6H). ¹³C NMR (CDCl₃): 177.54, 60.49,41.87, 39.22, 33.97, 28.63, 25.26, 14.34.

Ethyl 5-Bromo-2-methyl-2-phenyl-pentanoate (205b). Under Ar-atmosphere,to a solution of ethyl phenylacetate (42.4 g, 0.26 mol) and DMPU (5 mL)in THF (250 mL) was added dropwise a solution of LDA (2 M, 135 mL, 0.27mol) at −78° C. The mixture was stirred for 2 h, before methyl iodide(41.40 g, 0.29 mol) was added in a single portion. The mixture wasstirred overnight and allowed to warm to room temperature. After coolingto −78° C., 1,3-dibromopropane (72.7 g, 0.36 mol) was added and themixture was allowed to stir overnight, gradually warming to roomtemperature. The mixture was hydrolyzed by consecutive addition of ice(200 g), saturated aqueous NH₄Cl solution (400 mL), and concd HCl (100mL), and extracted with ethyl acetate (2×200 mL). The organic layerswere dried over over anhydrous MgSO₄, and distilled under vacuum to give205b as colorless oil (88.6 g, 59%). Bp 123-128° C./0.25 mmHg. ¹H NMR(CDCl₃): 7.20-7.10 (m, 5H), 4.12 (q, 2H, J=7.2), 3.35 (t, 2H, J=6.9),2.18-2.00 (m, 2H), 1.77-1.72 (m, 2H), 1.56 (s, 3H), 1.18 (t, 3H, J=6.9).¹³C NMR (CDCl₃): 175.9, 143.4, 128.5, 126.9, 126.0, 61.0, 49.8, 38.2,34.0, 28.5, 22.8, 14.2.

Ethyl 6-Bromo-2,2-dimethylhexanoate (205c). This compound was preparedas described in lit. (Ackerley, N. et al. J. Med. Chem. 1995, 38,1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818). Bp65° C./0.15 mmHg (lit. 86° C./0.2 mmHg; lit. 62-64° C./0.40 mmHg). ¹HNMR (CDCl₃): 4.15 (q, 2H, J=7.1), 3.41 (t, 2H, J=6.7), 1.85 (qv, 2H,J=6.7), 1.60-1.45 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (t, 3H, J=7.1), 1.20(s, 6H). ¹³C NMR (CDCl₃): 177.3, 60.0, 41.8, 39.4, 33.2, 32.9, 24.9,23.34, 14.02.

Ethyl 6-Bromo-2-methyl-2-phenylhexanoate (205d). A solution of LDA (14mL, 28 mmol, 2.0 M in heptane) was added dropwise to a stirred solutionof 202 (5.0 g, 28.06 mmol) in anhydrous THF (50 mL) at −78° C. After 1h, the reaction mixture was added to a −78° C. cold solution of1,4-dibromobutane (10.06 g, 23.1 mmol) in THF. After the addition ofDMPU (5 mL), the reaction mixture was stirred for 1 h, then warmed toroom temperature and stirred overnight. The mixture was poured intosaturated aqueous NH₄Cl solution (500 mL) and extracted with ethylacetate (4×100 mL). The combined organic phases were washed with brine(100 mL), 1 M HCl (50 mL), saturated aqueous NaHCO₃ solution (50 mL),and brine (100 mL). The solution was dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was distilled to give 205d as an oil(7.16 g, 99%). Bp 130-131° C./0.2 mmHg. ¹H NMR (CDCl₃), δ (ppm):7.40-7.15 (m, 5H), 4.13 (q, 2H, J=6.7), 3.36 (t, 2H, J=6.7), 2.02 (m,2H), 1.86 (m, 2H), 1.56 (s, 3H), 1.34 (m, 2H), 1.18 (t, 3H, J=6.7). ¹³CNMR (CDCl₃), δ (ppm): 176.13, 143.91, 128.51, 126.81, 126.03, 60.93,50.22, 38.53, 33.56, 33.30, 23.58, 22.77, 14.22. HRMS (FAB): Calcd forC₁₅H₂₁ ⁷⁹BrO₂ (MH⁺): 313.0803, found 313.0786.

Ethyl 6-Bromo-2-methyl-2-p-tolylhexanoate (205e). This compound wasprepared according to the procedure for 205d to give 205e (22.0 g, 90%)as an oil. Bp 128-130° C./0.2 mmHg). ¹H NMR (CDCl₃): δ (ppm) 7.19 (d,2H, J=8.2 Hz), 7.12 (d, 2H, J=8.2 Hz), 4.13 (q, 2H, J=7.2 Hz), 3.37 (t,J=6.6 Hz, 2H), 2.32 (s, 3H), 2.10-1.80 (m, 4H), 1.54 (s, 3H), 1.36 (m,2H), 1.19 (t, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃): δ (ppm) 176.26, 140.92,136.35, 129.21, 125.89, 60.88, 49.82, 38.53, 33.61, 33.33, 23.59, 22.78,21.07, 14.25. HRMS (FAB, nba): Calcd for (C₁₆H₂₃BrO₂) 327.0959, found327.0975.

6-Bromo-2-(4-isobutylphenyl)-2-methylhexanoic acid ethyl ester (205f).Under nitrogen atmosphere and at −78° C., to a solution of 204 (10.5 g,44.8 mmol) in anhydrous THF (150 mL) was added a solution of LDA (2.0 M,28 mL, 56 mmol) and the mixture was stirred for 1 h. 1,4-Dibromobutane(25 mL, 37.5 g, 175 mmol) was then added dropwise over 30 min and thesolution allowed to warm to room temperature over 5 h. After stirring atroom temperature for an additional 16 h, the reaction was hydrolyzedwith water (100 mL) and extracted with Et₂O (2×100 mL). The combinedorganic layers were washed with 10% HCl (2×100 mL), saturated aqueousNaHCO₃ solution (100 mL) and water (100 mL). After drying with Na₂SO₄ (5g), filtration and concentration, the crude product was purified byflash chromatography (silica gel; ethyl acetate/hexanes=5/95) and driedin high vacuo (0.5 mmHg) at 150° C. for 30 min, affording 205f (14.49 g,88%) as a clear, viscous oil. ¹H NMR (CDCl₃): δ 7.19 (d, 2H, J=8.0),7.08 (d, 2H, J=8.0), 4.11 (q, 2H, J=7.0), 3.35 (t, 2H, J=6.8), 2.43 (d,2H, J=7.3), 2.10-1.92 (m, 1H), 1.92-1.78 (m, 4H), 1.53 (s, 3H),1.40-1.28 (m, 2H), 1.17 (t, 3H, J=7.0), 0.88 (d, 6H, J=6.8). ¹³C NMR(CDCl₃): δ 176.17, 141.12, 140.04, 129.14, 125.64, 60.77, 49.80, 44.99,38.52, 33.51, 33.26, 30.22, 23.55, 22.69, 22.50, 14.19. HRMS (LSIMS,nba): Calcd for C₁₉H₃₀O₂Br (MH⁺): 369.1429, found: 369.1445.

Ethyl 7-Bromo-2,2-dimethylheptanoate (205g). Under argon atmosphere, asolution of 1,5-dibromopentane (500 g, 2.2 mol) and ethyl isobutyrate(221 g, 1.9 mol) in anhydrous THF (4 L) was chilled in a dry ice/acetonebath to −78° C. Over a 40 min period, LDA solution in THF (1.8 M, 1 L,1.8 mol) was added dropwise. After the addition, the solution wasallowed to stir overnight and gradually warm to room temperature.Careful quenching of the excess base by slow addition of saturatedaqueous NH₄Cl solution (3 L) furnished a two-phase mixture. The organiclayer was separated and evaporated under vacuum to a minimum volume (ca.1 L). The organic residue was recombined with the aqueous layer and theresulting mixture was extracted with ethyl acetate (3×1 L). The combinedethyl acetate layers were then washed with 1 N HCl (5 L), water (3 L)and saturated aqueous NaHCO₃ solution (4 L) before drying over anhydrousMgSO₄. Concentration in vacuo gave crude material (468.7 g), which wasthen purified by distillation affording 205g (208.7 g, 44%) as acolorless oil. Bp 106-108° C./0.01 mmHg. ¹H NMR (CDCl₃): δ 4.11 (q, 2H,J=7.2), 3.39 (t, 2H, J=6.8), 1.85 (m, 2H), 1.56-1.35 (m, 4H), 1.24 (t,3H, J=7.2), 1.31-1.19 (m, 2H), 1.16 (s, 6H). ¹³C NMR (CDCl₃): δ 177.9,60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (EI): Calcdfor C₁₁H₂₂BrO₂ (MH⁺) 265.0803, found 265.0810.

Ethyl 7-Bromo-2-methyl-2-phenylheptanoate (205h). Under N₂ atmosphere, asolution of LDA (2.0 M in heptane/THF/ethylbenzene, 1.85 mL, 3.70 mol)was added dropwise to a stirred solution of 202 (660 g, 3.70 mol) inanhydrous THF (6.6 L) over 30 min at −78° C. After 1 h,1,5-dibromopentane (1390 g, 6.05 mol) was added, followed by theaddition of DMPU (660 mL). The reaction mixture was stirred for 1 h,then warmed to room temperature and stirred overnight. The mixture waspoured into saturated aqueous NH₄Cl solution (24 L) and extracted withethyl acetate (4×6.7 L). The combined organic layers were washed withbrine (9 L), 1 N HCl (6 L), saturated aqueous NaHCO₃ solution (6 L), andbrine (6 L). The solution was dried over MgSO₄ and concentrated invacuo. The residue was distilled in high vacuo to yield 205h (700 g,58%) as a yellowish oil. Bp 140-145° C./0.3 mmHg. ¹H NMR (CDCl₃): δ7.30-7.20 (m, 5H), 4.09 (m, 2H), 3.34 (t, 2H, J=6.9), 2.05-1.80 (m, 4H),1.53 (s, 3H), 1.43-1.14 (m, 4H), 1.16 (t, 3H, J=6.6). ¹³C NMR (CDCl₃): δ176.03, 143.99, 128.33, 126.60, 125.89, 60.68, 50.11, 39.03, 33.75,32.51, 28.59, 23.93, 22.78, 14.10. HRMS (LSIMS, nba): Calcd forC₁₆H₂₄BrO₂ (MH⁺): 327.0960, found: 327.0952. HPLC: 91.2% pure.

Ethyl 8-bromo-2,2-dimethyloctanoate (205i). Under N₂ atmosphere, asolution of LDA (2.0 M in heptane/THF/ethylbenzene, 2.94 L, 5.9 mol) wasadded dropwise to a stirred solution of ethyl isobutyrate (720 g, 6.2mol) in anhydrous THF (4.7 L) at−45° C. After 1 h, 1,6-dibromohexane(2400 g, 9.8 mol) was added dropwise, followed by the addition of DMPU(320 mL). The reaction mixture was stirred for 1 h and then allowed towarm to room temperature overnight. Saturated NH₄Cl solution (3 L) wasadded and the mixture was extracted with ethyl acetate (3×6 L). Thecombined organic layers were washed with brine (4.5 L), 1 M aqueous HCl(6 L), saturated NaHCO₃ solution (6 L), and brine (4.5 L). The solutionwas dried over anhydrous MgSO₄ and concentrated in vacuo. The residuewas distilled under high vacuo to furnish 205i (856 g, 52%) as a lightyellowish oil. Bp 95-100° C./0.2 mmHg. ¹H NMR (CDCl₃): δ (ppm): 4.13 (q,J=7.1, 2H), 3.39 (t, J=6.9, 2H), 1.92-1.75 (m, 2H), 1.58-1.25 (m, 8H),1.25 (t, J=7.1, 3H), 1.12 (s, 6H). ¹³C NMR (CDCl₃=77.52 ppm): δ (ppm):177.62, 60.01, 42.08, 40.50, 33.63, 32.68, 29.13, 27.93, 25.00, 24.66,14.22. HRMS (LSIMS, nba): Calcd for C₁₂H₂₄BrO₂ (MH⁺): 279.0960, found:279.0957. GC: 76.4% pure.

Ethyl 9-bromo-2,2-dimethylnonanoate (205j). Under N₂ atmosphere at 0°C., LDA (2 M solution in THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol)was added dropwise to a mixture of ethyl isobutyrate (3.5 mL, 3.0 g,25.9 mmol) and 1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL)over 1.5 h, while keeping the temperature below 5° C. After 3 h, themixture was poured into ice-cold saturated aqueous NH₄Cl solution (150mL). The layers were separated and the aqueous phase was extracted withEt₂O (3×100 mL). The combined organic layers were washed with aqueousHCl (1 M, 100 mL), saturated aqueous NaHCO₃ solution (100 mL) and brine(100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue (12.4 g) was purified twice by column chromatography (heptane:ethyl acetate=40:1) to give 205j (3.42 g, 45%) as a colorless liquid. ¹HNMR (CDCl₃): δ (ppm): 4.11 (q, J=7.2, 2H), 3.40 (t, J=6.9, 2H), 1.85(quintet, J=6.9, 2H), 1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20(m, 6H), 1.24 (t, J=7.2, 3H), 1.15 (s, 6H). ¹³C-NMR (CDCl₃): δ (ppm):177.8, 60.0, 42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2×), 24.7,14.1. HRMS: Calcd for C₁₃H₂₅BrO₂ (M⁺): 292.1038, found: 292.1034.

Representative Procedure for the Reduction of Ethyl ω-Bromoalkanoateswith Lithium Borohydride and Methanol:6-Bromo-2-methyl-2-p-tolylhexan-1-ol (206e). Methanol (3.14 g, 98.0mmol) was added dropwise to a stirred suspension of LiBH₄ (2.19 g, 100.6mmol) in anhydrous CH₂Cl₂ (50 mL) under N₂ atmosphere. After theaddition of 5e (22.0 g, 67.2 mmol), the reaction mixture was heated toreflux overnight. The reaction mixture was cooled to 5° C. andhydrolyzed with ice (ca. 40 g) and saturated aqueous NH₄Cl solution (150mL) for 1 h. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (3×200 mL). The combined organic layers werewashed with saturated aqueous NH₄Cl solution (3×150 mL), dried overMgSO₄ and concentrated in vacuo to give 206e (18.44 g, 96%) as an oil,which was used without further purification for the next step. ¹H NMR(CDCl₃): δ 7.25-7.00 (m, 4H), 3.68-3.50 (m, 1H), 3.49-3.35 (m, 1H),3.34-3.21 (t, 2H, J=6.9), 2.31 (s, 3H), 1.88-1.51 (m, 4H), 1.51-1.40 (m,2H), 1.31 (s, 3H), 1.20-1.00 (m, 1H). ¹³C NMR (CDCl₃): δ 141.49, 135.74,129.47, 126.63, 72.54, 43.03, 37.53, 33.69, 33.51, 22.66, 21.58, 20.98.HRMS (LSIMS, nba): Calcd for C₁₄H₂₀Br (MH⁺-H₂O): 267.0748, found:267.0750.

5-Bromo-2,2-dimethylpentan-1-ol (206a). According to the procedure givenfor the synthesis of 206e, 205a (94.0 g, 0.37 mol) was reduced withLiBH₄ (12.97 g, 0.60 mol) and methanol (19.04 g, 0.60 mol) in CH₂Cl₂(400 mL) to give 206a (78.0 g, 100%) as an oil. ¹H NMR (DMSO-d₆): δ 4.42(s, 1H), 3.45 (t, 2H, J=6.6), 3.08 (s, 2H), 1.84-1.69 (m, 2H), 1.27 (t,2H, J=8.3), 0.78 (s, 6H). ¹³C NMR (DMSO-d₆): δ 69.7, 36.9, 35.7, 34.5,27.4, 24.0.

5-Bromo-2-methyl-2-phenylpentan-1-ol (206b). According to the proceduregiven for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reducedwith LiBH₄ (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) inanhydrous CH₂Cl₂ (150 mL) to give 206b (20.0 g, 98%) as an oil. ¹H NMR(CDCl₃): δ 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H,J=6.0), 1.96-1.44 (m, 5H), 1.32 (s, 3H). ¹³C NMR (CDCl₃): δ 144.25,128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS(LSIMS, nba): Calcd for C₁₂H₁₆Br (MH⁺-H₂O): 239.0435, found: 239.0444.

6-Bromo-2,2-dimethylhexanol (206c). According to the procedure describedfor the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38,1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c(500.0 g, 2.0 mol) was reacted with LiBH₄ (65.0 g, 3.0 mol) and methanol(95.0 g, 3.0 mol) in CH₂Cl₂ (6.0 L) to afford 206c (417.0 g, 99%) as anoil. ¹H NMR (CDCl₃): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH),3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20(m, 2H), 0.85 (s, 6H). ¹³C NMR (CDCl₃) δ 71.4, 37.5, 34.9, 33.9, 33.4,23.7, 22.4.

6-Bromo-2-methyl-2-phenylhexan-1-ol (206d). According to the proceduregiven for the synthesis of 206e, 205d (52.0 g, 166.0 mmol) was reactedwith LiBH₄ (5.4 g, 247.9 mmol) and methanol (8.2 g, 255.9 mmol) inCH₂Cl₂ (180 mL) to afford 206d (38.0 g, 84%) as an oil. ¹H NMR (CDCl₃):δ 7.5-7.1 (m, 5H), 3.60 (d, 1H, J=10.8), 3.53 (d, 1H, J=10.8), 3.34 (t,2H, J=7.0), 1.90-1.78 (m, 3H), 1.62-1.26 (m, 3H), 1.35 (s, 3H), 1.14 (m,1H). ¹³C NMR (CDCl₃): δ 144.4, 128.4, 126.5, 126.1, 72.4, 43.2, 37.4,33.5, 33.3, 22.5, 21.4.

7-Bromo-2,2-dimethylheptan-1-ol (206g). According to the method for thesynthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH₄ (5.55g, 0.25 mol) and methanol (7.75 g, 0.24 mol) in CH₂Cl₂ (200 mL) to give206g (36.2 g, 98%) as a colorless, viscous oil. ¹H NMR (CDCl₃): δ 3.41(t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H),0.86 (s, 6H). ¹³C NMR (CDCl₃): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2,24.0, 23.2. HRMS (LSIMS, nba): Calcd for C₉H₁₈Br (MH⁺-H₂O): 205.0592,found: 205.0563.

7-Bromo-2-methyl-2-phenylheptan-1-ol (206h). According to the proceduregiven for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reducedwith LiBH₄ (5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) inanhydrous CH₂Cl₂ (390 mL). After the typical workup, crude 206h (51.0 g,98%) was obtained as a yellowish oil, which was used without furtherpurification for the next step. ¹H NMR (CDCl₃): δ 7.25-7.08 (m, 5H),3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz),1.92-0.95 (m, 9H), 1.28 (s, 3H). ¹³C NMR (CDCl₃): δ 144.77, 128.51,126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59.HRMS (EI): Calcd for C₁₄H₂₁BrO (M⁺): 284.0776, found: 284.0787.

Representative Procedure for the THP-Protection of ω-Bromoalkanols:2-(6-Bromo-2-methyl-2-phenylhexyloxy)-tetrahydropyran (207d). Under N₂atmosphere and cooling with an ice bath, 3,4-dihydro-2H-pyran (33.86 g,0.40 mol) was added dropwise to a stirred solution of 206d (88.0 g, 0.32mol) and p-toluenesulfonic acid hydrate (0.05 g, 0.03 mmol) in CH₂Cl₂(700 mL). After the addition, the reaction mixture was allowed to warmto room temperature and stirred overnight. The solution was filteredthrough aluminum oxide (160 g) and the aluminum oxide was washed withCH₂Cl₂ (800 mL). The filtrate was concentrated in vacuo and purified byflash chromatography on silica gel (hexanes/ethyl acetate=10/1) to give207d (80.0 g, 70%) as an oil. ¹H NMR (CDCl₃): δ 7.40-7.14 (m 10H), 4.53(t, 1H, J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H,J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33 (t,4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s, 6H),1.34-1.10 (m, 6H). ¹³C NMR (CDCl₃=77.0 ppm): δ 145.67, 127.91, 127.91,126.39, 126.37, 125.7, 98.95, 98.81, 76.11, 76.07, 62.78, 61.77, 61.66,41.88, 41.78, 37.93, 37.75, 33.50, 33.44, 30.59, 30.44, 25.41, 25.37,22.77, 22.71, 22.62, 19.65, 19.23, 19.15. HRMS (LSIMS, nba): Calcd forC₁₈H₂₈BrO₂ (MH⁺): 355.1272, found: 355.1272.

2-(5-Bromo-2,2-dimethylpentyloxy)-tetrahydropyran (207a). According tothe procedure for the preparation of 207d, 206a (78.0 g, 0.40 mol) wasreacted with 3,4-dihydro-2H-pyran (41.5 g, 0.49 mol) andp-toluenesulfonic acid hydrate (0.42 g, 2.2 mmol) in CH₂Cl₂ (0.5 L) toyield 207a (101.0 g, 90%) as a pale-yellow oil, which was used withoutfurther purification. ¹H NMR (CDCl₃): δ 4.55 (t, 1H, J=2.9), 3.83 (m,1H), 3.51 (m, 1H), 3.47 (d, 1H, J=9.0), 3.38 (t, 2H, J=6.8), 2.98 (d,1H, J=9.0), 1.94-1.75 (m, 2H), 1.75-1.44 (m, 6H), 1.40 (t, 2H, J=8.5),0.91 (s, 3H), 0.90 (s, 3H). ¹³C NMR (CDCl₃): δ 99.01, 76.17, 61.85,37.89, 34.66, 34.04, 30.62, 27.92, 25.60, 24.64, 24.56, 19.41. HRMS(LSIMS, nba): Calcd for C₁₂H₂₄BrO₂ (MH⁺): 279.0960, found: 279.0955.

2-(5-Bromo-2-methyl-2-phenylpentyloxy)-tetrahydropyran (207b). Accordingto the method described for the synthesis of 207d, 206b (20.0 g, 77.8mmol) was treated with 3,4-dihydro-2H-pyran (8.2 g, 96.5 mmol) andp-toluenesulfonic acid hydrate (0.57 g, 3.0 mmol) in CH₂Cl₂ (350 mL) toafford 207b (25.2 g, 95%) as an oil, which was used without furtherpurification. ¹H NMR (CDCl₃): 7.26-7.08 (m, 5H), 4.45 (m, 1H), 3.72 (m,1H), 3.58 (m, 1H), 3.35-3.05 (m, 2H), 3.28 (t, 2H, J=6.6), 1.95-1.39 (m,10H), 1.25 (s, 3H). ¹³C NMR (CDCl₃): δ 145.38, 128.15, 126.51, 126.03,99.06, 98.92, 76.20, 61.91, 61.80, 41.82, 41.74, 37.58, 37.43, 34.65,30.61, 27.88, 25.58, 23.03, 22.90, 19.39, 19.32. HRMS (LSIMS, nba):Calcd for C₁₇H₂₆O₂Br (MH⁺): 341.1116, found: 341.1127.

2-(6-Bromo-2,2-dimethylhexyloxy)-tetrahydropyran (207c). According tothe procedure for the preparation of 207d, (Ackerley, N. et al. J. Med.Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30,1812-1818) 206c (521.0 g, 2.49 mol) was reacted with3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acidhydrate (3.13 g, 16 mmol) in CH₂Cl₂ (2.2 L) to yield 207c (603.0 g, 83%)as a pale-yellow oil, which was used without further purification. ¹HNMR (CDCl₃): δ 4.55 (t, 1H, J=3.3), 3.84 (m, 1H), 3.50 (m, 1H), 3.47 (d,1 H , J=9.0), 3.42 (t, 2H, J=6.7), 2.99 (d, 1H, J=9.0), 1.88 (m, 2H),1.75-1.33 (m, 10H), 0.91 (s, 3H), 0.90 (s, 3H). ¹³C NMR (CDCl₃): δ99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80,24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C₁₃H₂₅BrO₂ (MH⁺):293.1116, found: 293.1128.

2-(6-Bromo-2-methyl-2-p-tolylhexyloxy)-tetrahydropyran (207e). Accordingto the method described for the synthesis of 207d, 206e (18.2 g, 63.8mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) andp-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH₂Cl₂ (300 mL) togive 207e (22.0 g, 93%) as an oil, which was used without furtherpurification. ¹H NMR (CDCl₃): δ 7.25-7.05 (m, 4H), 4.60-4.48 (m, 1H),3.82 (m, 2H), 3.48-3.37 (m, 2H), 3.35-3.26 (m, 2H), 2.30 (s, 3H),1.90-1.40 (m, 11H), 1.34 (s, 3H), 1.40-1.08 (m, 1H). ¹³C NMR (CDCl₃): δ142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67,41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41,19.37. HRMS (LSIMS, nba): Calcd for C₁₉H₃₀O₂Br (MH⁺): 369.1429, found:369.1451.

2-(7-Bromo-2,2-dimethylheptyloxy)-tetrahydropyran (207g). According tothe method described for the synthesis of 207d, 206g (36.0 g, 161 mmol)was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) andp-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH₂Cl₂ (60 mL).After filtration through neutral aluminum oxide (200 g) andconcentration, the crude product was purified by column chromatography(silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%)as an oil. ¹H NMR (CDCl₃): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H),3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m,7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). ¹³C NMR (CDCl₃): δ 99.3, 76.6,62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS(LSIMS, gly): Calcd for C₁₄H₂₈BrO₂ (MH⁺): 307.1272, found: 307.1245.

2-(7-Bromo-2-methyl-2-phenylheptyloxy)-tetrahydropyran (207h). Accordingto the method described for the synthesis of 207d, 206h (51.0 g, 179mmol) was reacted with 3,4-dihydro-2H-pyran (18.80 g, 223 mmol) andp-toluenesulfonic acid hydrate (1.21 g, 6.36 mmol). Filtration throughaluminum oxide (370 g) and concentration in vacuo afforded 207h (48.75g, 76%) as a yellowish oil. ¹H NMR (CDCl₃): δ 7.35-7.17 (m, 10H), 4.53(m, 1H), 4.49 (m, 1H), 3.82 (m, 2H), 3.79 (m, 1H), 3.68-3.60 (m, 2H),3.45-3.35 (m, 2H), 3.32 (t, 4H, J=6.9), 1.82-1.18 (m, 28H), 1.35 (s,6H). ¹³C NMR (CDCl₃): δ 146.12, 128.11, 126.66, 125.89, 99.18, 99.04,76.46, 62.02, 61.83, 42.17, 42.07, 38.91, 38.73, 34.12, 32.80, 30.70,29.04, 25.66, 23.33, 22.97, 22.89, 19.49, 19.39. HRMS (LSIMS, nba):Calcd for C₁₉H₃₀BrO₂ (MH⁺): 369.1429, found: 369.1430.

6. BIOLOGICAL ASSAYS 6.1. Effects of Illustrative Compounds of theInvention on the In Vitro Lipid Synthesis in Isolated Hepatocytes

Compounds were tested for inhibition of lipid synthesis in primarycultures of rat hepatocytes. Male Sprague-Dawley rats were anesthetizedwith intraperitoneal injection of sodium pentobarbital (80 mg/kg). Rathepatocytes were isolated essentially as described by the method ofSeglen (Seglen, P. O. Hepatocyte suspensions and cultures as tools inexperimental carcinogenesis. J. Toxicol. Environ. Health 1979, 5,551-560). Hepatocytes were suspended in Dulbecco's Modified EaglesMedium containing 25 mM D-glucose, 14 mM HEPES, 5 mM L-glutamine, 5 mMleucine, 5 mM alanine, 10 mM lactate, 1 mM pyruvate, 0.2% bovine serumalbumin, 17.4 mM non-essential amino acids, 20% fetal bovine serum, 100mM insulin and 20 μg/mL gentamycin) and plated at a density of 1.5×10⁵cells/cm² on collagen-coated 96-well plates. Four hours after plating,media was replaced with the same media without serum. Cells were grownovernight to allow formation of monolayer cultures. Lipid synthesisincubation conditions were initially assessed to ensure the linearity of[1-¹⁴C]-acetate incorporation into hepatocyte lipids for up to 4 hours.Hepatocyte lipid synthesis inhibitory activity was assessed duringincubations in the presence of 0.25 μCi [1-¹⁴C]-acetate/well (finalradiospecific activity in assay is 1 Ci/mol) and 0, 1, 3, 10, 30, 100 or300 μM of compounds for 4 hours. At the end of the 4-hour incubationperiod, medium was discarded and cells were washed twice with ice-coldphosphate buffered saline and stored frozen prior to analysis. Todetermine total lipid synthesis, 170 μl of MicroScint-E® and 50 μl waterwas added to each well to extract and partition the lipid solubleproducts to the upper organic phase containing the scintillant. Lipidradioactivity was assessed by scintillation spectroscopy in a PackardTopCount NXT. Lipid synthesis rates were used to determine the IC₅₀s ofthe compounds that are presented in Table 6 and 7. TABLE 6 Effect ofCyclo-alkyl Ccompounds on Lipid Synthesis in Primary Rat Hepatocytes.95% Confidence IC₅₀ Interval Compound # (μm) Lower Upper r^(2a) m n R R1R2 R3 R4 R5 107c 0.6 0.3 0.9 0.98 4 4 CO₂H CO₂H Me Me cyclo-Propyl 107d0.3 0.1 5 0.98 4 4 CO₂H CO₂H cyclo-Propyl cyclo-Propyl 107e 6 5 8 0.95 44 CO₂H CO₂H Me Me cyclo-Butyl 107f 121 11 1268 0.89 4 4 CO₂H CO₂Hcyclo-Butyl cyclo-Butyl 107g 113 7 1794 0.95 4 4 CO₂H CO₂H cyclo-Pentylcyclo-Pentyl 106d 35 26 48 0.99 4 4 CO₂tBu CO₂tBu cyclo-Propylcyclo-Propyl 107k 1 0.7 1.4 0.94 5 5 CO₂H CO₂H Me Me cyclo-Propyl 107l0.5 0.4 0.7 0.99 5 5 CO₂H CO₂H cyclo-Propyl cyclo-Propyl 107m 2 2 2 0.995 5 CO₂H CO₂H cyclo-Pentyl cyclo-Pentyl 107n 10 4 21 0.97 7 7 CO₂H CO₂HMe Me Me Me 106n 13 4 46 0.93 7 7 CO₂Et CO₂Et Me Me Me Me^(a)r² is the goodness of fit of the data to the non-linear sigmoidalmodel.

TABLE 7 Effect of Keto-diacids and -Diols on Lipid Synthesis in PrimaryRat Hepatocytes. 95% Confidence Interval Compound IC₅₀ (μM) Lower Upperr² 210c

3 2 4 0.93 210e

100-300^(a) 210f

100-300^(a) 210g

3 3 3 0.99 210i

9 8 9 1 210j

5 2 11  0.98 214a

27  21  35  0.94 214b

100-300^(a) 214c

4 3 7 0.91 214d

100-300^(a) 214e

100-300^(a) 214g

3 3 5 0.94 214h

93  60  144  0.88 214i

2 1 8 0.97 217

 3-10^(a) 218

1 1 2 0.84 219

2 2 3 0.94 225

8 7 11  0.97 226

3 3 4 0.96 232

52 32  83  0.91^(a)The confidence of the IC₅₀ estimate is insufficient to assign avalue.

6.2. Effects of Illustrative Compounds of the Invention on NonHDLCholesterol, HDL Cholesterol, Triglyceride Levels, Glycemic ControlIndicators and Body Weight Control in Obese Female Zucker Rats

Ten- to twelve-week old (400-500 grams) female Zucker fatty rats Cr1:(Zuc)-faBR were obtained from Charles River Laboratories. Animals wereacclimated to the laboratory environment for seven days. During theacclimation and study period, animals were housed by group in shoeboxpolycarbonate cages on Cellu-Dri bedding. The temperature and humidityin the animals' quarters (68-78° F.; 30-75% RH) were monitored and theairflow in the room was sufficient to provide several exchanges per hourwith 100% fresh filtered air. An automatic timing device provided analternating 12-hour cycle of light and dark. Rats received pelletedPurina Laboratory Rodent Chow® (5001) prior to and during the drugintervention period except for a 6-hour phase prior to blood sampling.Fresh water was supplied ad libitum via an automatic watering system.Compounds were dissolved, suspended by mixing in a dosing vehicleconsisting of 1.5% carboxymethylcellulose/0.2% Tween 20 or 20% ethanoland 80% polyethylene glycol-200 [v/v]. Dose volume of vehicle or vehicleplus each compound was set at 0.25% of body weight in order to deliverthe appropriate dose. Doses were administered daily by oral gavage,approximately between 8-10 AM. Regarding blood sampling, animals werefasted for 6 hours prior to all blood collections. Prior to and after 7days of dosing, a 1.0- to 2.0-mL sample of blood was collected byadministering O₂/CO₂ anesthesia and bleeding from the orbital venousplexus. Following 14 days of dosing, blood was collected by cardiacpuncture after euthanasia with CO₂. All blood samples were processed forseparation of serum and stored at −80° C. until analysis. Commerciallyavailable kits were used to determine serum triglycerides (RocheDiagnostic Corporation, Kit No. 148899 or Boehringer Mannheim, Kit No.1488872), total cholesterol (Roche Diagnostic Corporation, Kit No.450061), non-esterified fatty acids (Wako Chemicals, Kit No. 994-75409)and β-hydroxybutyrate (Wako Chemicals, Kit No. 417-73501 or Sigma Kit.No. 310-0) on a Hitachi 912 Automatic Analyzer (Roche DiagnosticCorporation). In some instances, an in-house cholesterol reagent wasused to determine total serum cholesterol levels. Serum lipoproteincholesterol levels were determined by lipoprotein profile analysis.Lipoprotein profiles were analyzed using gel-filtration chromatographyon a Superose 6HR (1×30 cm) column equipped with on-line detection oftotal cholesterol as described by Kieft et al (Kieft, K. A.; Bocan, T.M.; Krause, B. R. Rapid on-line determination of cholesteroldistribution among plasma lipoproteins after high-performance gelfiltration chromatography. J. Lipid Res. 1991, 32, 859-866.). The totalcholesterol content of each lipoprotein was calculated by multiplyingthe independent values determined for serum total cholesterol by thepercent area of each lipoprotein in the profile. The percent body weightgain and the ratio of liver to body weight is also determined. Selecteddata are shown as absolute values or as a percent change of thepretreatment values in Tables 8 and 9. TABLE 8 Effect of Cyclo-alkylCompounds in Female Obese Zucker Rats. Serum Variables (Percent Changefrom Pre-Treatment)^(a) NonHDL- HDL- Compound Dose No. CholesterolCholesterol TG # (mg/kg) animals 1 wk 2 wk 1 wk 2 wk 1 wk 2 wk m n R R1R2 R3 R4 R5 107c 100 3 −84 −20 104 248 −93 −64 4 4 CO₂H CO₂H Me Mecyclo-Propyl 107d 100 3 22 63 180 260 −51 −28 4 4 CO₂H CO₂H cyclo-Propylcyclo-Propyl 107e 100 4 4 28 30 60 −54 −51 4 4 CO₂H CO₂H Me Mecyclo-Butyl 107f 100 4 −32 −40 −1 10 −58 −59 4 4 CO₂H CO₂H cyclo-Butylcyclo-Butyl 107g 100 4 −68 −67 36 40 −67 −70 4 4 CO₂H CO₂H cyclo-Pentylcyclo-Pentyl 107k 100 4 −90 −99 43 84 −93 −98 5 5 CO₂H CO₂H Me Mecyclo-Propyl 107l 100 4 −92 −83 136 171 −95 −94 5 5 CO₂H CO₂Hcyclo-Propyl cyclo-Propyl 107m 100 4 −54 −32 12 27 −63 −48 5 5 CO₂H CO₂Hcyclo-Pentyl cyclo-Pentyl 107n 100 3 −80 −45 44 86 −85 −64 7 7 CO₂H CO₂HMe Me Me Me^(a)100% represents a 2-fold increase from pre-treatment value

TABLE 9 Effect of Keto-diacids and -Diols in Female Obese Zucker Rats.Serum Variables Percent Change from Pre-Treatment NonHDL- HDL- DoseCholesterol Cholesterol TG Compound (mg/kg) n 1 wk 2 wk 1 wk 2 wk 1 wk 2wk 210b

100 3 36 65 4 12 10 26 210c

100 5 −62 −41 54 78 −74 −69 210d

100 3 36 79 43 45 −36 −8 210e

30 4 0 47 0 10 −11 12 210f

100 3 −40 −44 11 62 −63 −66 210g

100 4 −98 −99 72 168 −93 −94 210j

100 3 −80 −46 44 86 −85 −63 214a

100 3 −23 28 24 2 −31 0 214b

100 4 −18 −32 −14 −11 −20 −17 214c

100 4 −23 −10 110 126 −54 −29 214d

30 2 −30 30 −1 −27 −24 20 214f

100 3 28 34 −5 6 −11 −15 214g

100 3 −91 −88 76 135 −92 −92 214h

100 5 29 9 2 10 24 1 214i

30 4 −50 −32 85 61 −58 −33 217

100 2 −26 4 46 48 −40 −11 218

30 4 17 −8 −18 −5 18 −7 219

100 2 −70 −78 78 78 −85 −87 225

30 4 −17 92 7 4 −2 −22 226

100 3 −30 −51 240 72 −65 −62 231

59 3 −43 34 2 7 −24 7 232

100 4 −15 −5 1 −11 −29 −8

Select compounds (214c, 210c, and 210g) were further evalutated in theZucker rat by performing a full dose response and measuring additionalscrum variables including markers for diabetes (Tables 10-12). TABLE 10Effect of daily 214 c oral treatment on serum lipid and glycemic controlvariables in female obese Zucker rats. Non-HDL-C HDL-C TG Dose (mg/dl)(mg/dl) (mg/dl) mg/kg n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk  0 3225 ± 3 36 ± 5^(a) 30 ± 4^(a) 48 ± 2 39 ± 2^(a) 41 ± 2^(a)  933 ± 69 1114± 97^(a) 1099 ± 86^(a) (+144) (+120) (−19) (−15) (+119) (+118)  3 9 24 ±3 25 ± 3 22 ± 2 48 ± 3 43 ± 4^(a) 39 ± 4^(a)  755 ± 89  800 ± 75  781 ±65 (−10) (−19) 10 18 25 ± 3 21 ± 2 25 ± 2 46 ± 3 52 ± 3^(a) 53 ± 4^(a) 777 ± 70  602 ± 37^(a)  730 ± 52 (+113) (+115) (−23) 30 26 30 ± 3 28 ±2 38 ± 5^(a) 43 ± 2 60 ± 3^(a) 61 ± 4^(a)  998 ± 85  726 ± 49^(a)  985 ±110 (+127) (+140) (+142) (−27) 100  29 31 ± 3 23 ± 1 32 ± 2 45 ± 3 78 ±5^(a) 79 ± 6^(a) 1051 ± 80  485 ± 29^(a)  702 ± 53^(a) (+173) (+176)(−54) (−33) NEFA Glucose Insulin Dose (mg/dl) (mg/dl) (ng/ml) mg/kg Pre1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk  0 1.2 ± 0.08  1.3 ± 0.06  1.6 ±0.12^(a) 125 ± 2 118 ± 3 116 ± 3 9.1 ± 0.6  8.7 ± 0.5  7.7 ± 0.5 (+133) 3 1.1 ± 0.08  1.2 ± 0.05  1.6 ± 0.13^(a) 118 ± 4 106 ± 2 103 ± 3 8.8 ±1.5  7.5 ± 0.8  7.8 ± 0.6 (+145) 10 1.2 ± 0.05 0.98 ± 0.08^(a)  1.0 ±0.10 112 ± 3 110 ± 2 110 ± 3 8.4 ± 0.6  7.5 ± 0.4  7.8 ± 0.5 (−18) 301.4 ± 0.06  1.1 ± 0.05^(a)  1.2 ± 0.10 111 ± 1 112 ± 13 120 ± 3 9.3 ±0.8  9.1 ± 0.6  9.8 ± 0.7 (−21) 100  1.4 ± 0.10 0.98 ± 0.04^(a) 0.94 ±0.04^(a) 114 ± 2 120 ± 5 118 ± 3 9.6 ± 0.8 10.9 ± 1.0 11.0 ± 0.9 (−30)(−33)^(a)p < 0.05 compared to pretreatment.Data are represented as mean ± SEM.Numbers in parentheses are the percent increases (+) or decreases (−) ofthe pretreatment control values.

TABLE 11 Effect of daily 210 c oral treatment on serum lipid andglycemic control variables in female obese Zucker rats. Non-HDL-C HDL-CTG Dose (mg/dl) (mg/dl) (mg/dl) mg/kg n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre1 wk 2 wk  0 12 40 ± 11 43 ± 10 29 ± 3 39 ± 3 39 ± 5 38 ± 4 1303 ± 2611333 ± 231 1140 ± 124  3 4 32 ± 4 24 ± 2 24 ± 3 31 ± 3 36 ± 1 33 ± 1 996 ± 188  775 ± 92  857 ± 103 10 4 40 ± 8 26 ± 4^(a) 27 ± 4 37 ± 10 47± 7 39 ± 5 1143 ± 373  692 ± 180  814 ± 205 (−35) 30 4 48 ± 4 37 ± 4^(a)43 ± 5 34 ± 5 53 ± 8^(a) 50 ± 9^(a) 1242 ± 144  826 ± 92^(a)  962 ± 118(−23) (+156) (+147) (−33) 100  11 31 ± 4 18 ± 3^(a) 22 ± 3^(a) 38 ± 3 66± 9^(a) 68 ± 10^(a)  964 ± 90  383 ± 49^(a)  440 ± 58^(a) (−42) (−29)(+174) (+179) (−60) (−54) NEFA Glucose Insulin Dose (mg/dl) (mg/ dl)(ng/ml) mg/kg Pre 1 wk 2 wk Pre 1 wk 2 wk Pre 1 wk 2 wk  0 1.5 ± 0.12 1.5 ± 0.09  1.4 ± 0.10 134 ± 6 124 ± 7 118 ± 3  9.8 ± 0.9  8.4 ± 0.66.8 ± 0.7^(a) (−31)  3 1.5 ± 0.14  1.2 ± 0.16  1.5 ± 0.27 108 ± 6  99 ±4 103 ± 3 10.4 ± 1.3 10.7 ± 0.8 8.6 ± 0.5 10 1.6 ± 0.15 0.92 ± 0.09^(a) 1.5 ± 0.28 113 ± 7 105 ± 3 113 ± 3 10.6 ± 1.5  7.7 ± 1.0^(a) 8.9 ± 1.3(−27) 30 1.4 ± 0.15  1.0 ± 0.11^(a)  1.1 ± 0.20 103 ± 2 115 ± 4 118 ± 8 7.7 ± 1.6  9.2 ± 1.3 8.5 ± 1.8 (−29) 100  1.2 ± 0.06 0.81 ± 0.07^(a)0.66 ± 0.06^(a) 110 ± 3 113 ± 6 122 ± 7  8.1 ± 0.9  9.0 ± 1.0 9.5 ± 0.9(−33) (−45)^(a)p < 0.05 compared to pretreatment.Data are represented as mean ± SEM.Numbers in parentheses are the percent increases (+) or decreases (−) ofthe pretreatment control values.

TABLE 12 Effect of daily 210 g oral treatment on serum lipid andglycemic control variables in female obese Zucker rats. Non-HDL-C HDL-CTG Dose (mg/dl) (mg/dl) (mg/dl) mg/kg n Pre 1 wk 2 wk Pre 1 wk 2 wk Pre1 wk 2 wk  0 27 20 ± 2 29 ± 3^(a) 28 ± 3^(a) 76 ± 5  66 ± 5^(a)  69 ±5^(a) 950 ± 55 1119 ± 82^(a) 1189 ± 92^(a) (+145) (+140) (−13) (−9)(+118) (+125)  3 18 22 ± 2 23 ± 2 25 ± 2 77 ± 5  75 ± 6  77 ± 8 905 ± 57 995 ± 50  833 ± 57 10 22 22 ± 1 22 ± 2 34 ± 3^(a) 86 ± 10 136 ± 11^(a)138 ± 8^(a) 863 ± 63  553 ± 35^(a)  865 ± 69 (+155) (+158) (+160) (−36)30 18 27 ± 3 14 ± 2^(a) 30 ± 2 62 ± 5 159 ± 12^(a) 208 ± 14^(a) 982 ± 75 213 ± 19^(a)  475 ± 38^(a) (−48) (+256) (+335) (−78) (−52) 100  15 26 ±2  2 ± 1^(a)  3 ± 1^(a) 66 ± 5 100 ± 8^(a) 141 ± 12^(a) 937 ± 77  69 ±5^(a)  78 ± 10^(a) (−92) (−88) (+151) (+213) (−93) (−92) NEFA GlucoseInsulin Dose (mg/dl) (mg/dl) (ng/ml) mg/kg Pre 1 wk 2 wk Pre 1 wk 2 wkPre 1 wk 2 wk  0 1.3 ± 0.06  1.3 ± 0.07  1.3 ± 0.07 129 ± 4 123 ± 2 120± 2  9.1 ± 0.5 10.1 ± 0.6 8.1 ± 0.6  3 1.3 ± 0.09 1 .1 ± 0.07^(a)  1.0 ±0.10^(a) 114 ± 3 117 ± 4 124 ± 4^(a)  8.6 ± 0.9 10.0 ± 1.0 7.3 ± 0.5(−15) (−23) (+108) 10 1.2 ± 0.08  1.0 ± 0.07^(a) 0.95 ± 0.08^(a) 120 ± 4122 ± 3 125 ± 4  9.9 ± 0.9 10.5 ± 1.1 9.1 ± 0.7 (−17) (−21) 30 1.3 ±0.07 0.88 ± 0.06^(a) 0.66 ± 0.03^(a) 119 ± 5 108 ± 4 130 ± 4  9.8 ± 0.9 6.4 ± 0.6^(a) 7.7 ± 0.9^(a) (−32) (−49) (−35) (−21) 100  1.4 ± 0.060.98 ± 0.08^(a) 0.66 ± 0.06^(a) 117 ± 3  92 ± 4^(a) 105 ± 3^(a) 11.9 ±1.0  6.4 ± 1.3^(a) 6.0 ± 0.8^(a) (−30) (−52) (−21) (−10) (−46) (−50)^(a)p < 0.05 compared to pretreatment.Data are represented as mean ± SEM.Numbers in parentheses are the percent increases (+) or decreases (−) ofthe pretreatment control values.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodimentswhich are functionally equivalent are within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art and are intended to fall within the appended claims.

1. A compound of a formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein (a) each occurrence of Z is independently CH₂, CH═CH,or phenyl, wherein each occurrence of m is independently an integerranging from 1 to 9, but when Z is phenyl then its associated m is 1;(b) G is (CH₂)_(x), CH₂CH═CHCH₂, CH═CH, CH₂₋phenyl-CH₂, or phenyl,wherein x is 2, 3, or 4; (c) W¹ and W² are independently L, V,C(R¹)(R²)—(CH₂)_(c-)C(R³)(R⁴)—(CH₂)_(n-)Y, or C(R¹)(R²)—(CH₂)_(c-)V,wherein c is 1 or 2 and n is an independent integer ranging from 0 to 4;(d) R¹ and R² are independently CO₂H, CO_(2(C) ₁₋C₆)alkyl, (C₁₋C₆)alkyl,(C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, or benzyl or when W¹ or W² isC(R¹)(R²)—(CH₂)_(c-)C(R³)(R⁴)—Y, then R¹ and R² can both be H, or R¹ andR² and the carbon to which they are both attached are taken together toform a (C₃-C₇)cycloakyl group; (e) R³ and R⁴ are independently H, OH,CO₂H, CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl,(C₁₋C₆)alkoxy, phenyl, benzyl, Cl, Br, CN, NO₂, or CF₃, with the provisothat when R¹ and R² are both H, then one of R³ or R⁴ is not H or R³ andR⁴ and the carbon to which they are both attached are taken together toform a (C₃-C₇)cycloakyl group; (f) L is C(R¹)(R²)CH₂)_(n-)Y; (g) V is

(h) Y is (C₁₋C₆)alkyl, OH, COOH, CHO, COOR⁵, SO₃H,

 where (I) R⁵ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁶ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁷ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; and  provided that: (i)if G is (CH₂)_(x), x is 4, each occurrence of Z is CH₂, each occurrenceof m is 4, and W¹ is —CH(CH₃)CO₂H, then W² is not the same as W¹; (ii)if G is CH₂-phenyl-CH₂, each occurrence of Z is CH₂, each occurrence ofm is 2, and W¹ is —C(CH₃)₂CH(CO₂CH₂CH₃)₂, then W² is not the same as W¹;(iii) if G is CH₂-phenyl-CH₂, each occurrence of Z is CH₂, eachoccurrence of m is 2, and W¹ is —C(CH₃)₂CH₂(CO₂CH₂CH₃), then W² is notthe same as W¹; (iv) if G is CH₂-phenyl-CH₂, each occurrence of Z isCH₂, each occurrence of m is 1, and W¹ is —COCH₂C(CH₃)₂CH₂CO₂H, then W²is not the same as W¹; (v) if G is (CH₂)_(x), x is 4, each occurrence ofZ is CH₂, each occurrence of m is 2, and W¹ is —C(phenyl)₂CH₂CO₂H, thenW² is not the same as W¹; (vi) if G is CH═CH, each occurrence of Z isCH₂, each occurrence of m is 1, and W¹ is —C(CH₃)₂CH₂(CO₂H), then W² isnot the same as W¹; and (vii) if G is phenyl, each occurrence of Z isCH₂, each occurrence of m is 1, and W¹ is —C(phenyl)₂CO₂H, then W² isnot the same as W¹.
 2. The compound of claim 1, wherein: (a) W¹ and W²are independently L, V, or C(R¹)(R²)—(CH₂)_(c-)V where c is 1 or 2; and(b) R¹ or R² are independently (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,(C₂₋C₆)alkynyl, phenyl, or benzyl.
 3. The compound of claim 1, whereinW¹ is L.
 4. The compound of claim 1, wherein W¹ is V.
 5. The compound ofclaim 1, wherein W¹ is C(R¹)(R²)—(CH₂)_(c-)C(R³)(R⁴)—(CH₂)_(n-)—Y. 6.The compound of claim 1, wherein W¹ is C(R¹)(R²)—(CH₂)_(c-)V.
 7. Thecompound of claim 1, wherein W¹ and W² are independent L groups.
 8. Thecompound of claim 7, wherein each occurrence of Y is independently(CH₂)_(n)OH, (CH₂)_(n)COOR⁵, or (CH₂)_(n)COOH.
 9. A compound of theformula Ia:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein (a) each occurrence of Z is independently CH₂ or CH═CH,wherein each occurrence of m is independently an integer ranging from 1to 9; (b) G is (CH₂)_(x), CH₂CH═CHCH₂, or CH═CH, where x is 2, 3, or 4;(c) W¹ and W² are independently L, V, or C(R¹)(R²)—(CH₂)_(c-)V, where cis 1 or 2; (d) each occurrence of R¹ and R² is independently CO₂H,CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,benzyl, or R¹ and R² and the carbon to which they are both attached aretaken together to form a (C₃₋C₇)cycloakyl group; (e) L isC(R¹)(R²)—(CH₂)_(n-)Y, where n is an independent integer ranging from 0to 4; (f) V is

(g) each occurrence of Y is independently (C₁₋C₆)alkyl, OH, COOH, CHO,(CH₂)_(n)COOR³, SO₃H,

 where (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁵ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; and  provided that: (i)if x is 4, each occurrence of Z is CH₂, each occurrence of m is 4, andW¹ is —CH(CH₃)CO₂H, then W² is not the same as W¹; (ii) if x is 4, eachoccurrence of Z is CH₂, each occurrence of m is 2, and W¹ is—C(phenyl)₂CH₂CO₂H, then W² is not the same as W¹.
 10. The compound ofclaim 9, wherein W¹ is L.
 11. The compound of claim 9, wherein W¹ is V.12. The compound of claim 9, wherein W¹ is C(R¹)(R²)—CH₂)_(c-)V.
 13. Thecompound of claim 9, wherein W¹ and W² are independent L groups.
 14. Thecompound of claim 13, wherein each occurrence of Y is independently OH,COOR³, or COOH.
 15. A compound of the formula Ib

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein: (a) each occurrence of m is independently an integerranging from 1 to 9; (b) x is 2, 3, or 4; (c) n is an independentinteger ranging from 0 to 4; (d) each occurrence of R¹ and R² isindependently CO₂H, CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl,(C₂₋C₆)alkynyl, phenyl, benzyl, or R¹ and R² and the carbon to whichthey are both attached are taken together to form a (C₃₋C₇)cycloakylgroup; (e) each occurrence of R¹¹ and R¹² is independently H, CO₂H,CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,benzyl, or R¹¹ and R¹² and the carbon to which they are both attachedare taken together to form a (C₃₋C₇)cycloakyl group; (f) each occurrenceof Y is independently (C₁₋C₆)alkyl, OH, COOH, CHO, COOR³, SO₃H,

 where (I) R³ is (C₁₋C₆)alkyl, (C₂-C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups; and (iii) each occurrence of R⁵ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl;  provided that: (i) ifx is 4 each occurrence of m is 4, and W¹ is —CH(CH₃)CO₂H, then W² is notthe same as W¹; (ii) if x is 4 occurrence of m is 2, and W¹ is—C(phenyl)₂CH₂CO₂H, then W² is not the same as W¹.
 16. The compound ofclaim 15, wherein each occurrence of Y is independently OH, COOR³, orCOOH.
 17. The compound of claim 16, wherein each R¹ or R² is the same ordifferent (C₁₋C₆)alkyl group.
 18. A compound of the formula Ic

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein: (a) each occurrence of m is an independent integerranging from 1 to 9; (b) x is 2, 3, or 4; (c) V is

 provided that: (i) if x is 4 each occurrence of m is 4, and W¹ is—CH(CH₃)CO₂H, then W² is not the same as W¹; and (ii) if x is 4 eachoccurrence of m is 2, and W¹ is —C(phenyl)₂CH₂CO₂H, then W² is not thesame as W¹.
 19. A compound according to claim 1, having the formula5-[2-(5-hydroxy-4,4-dimethyl-pentyloxy)-ethoxy]-2,2-dimethyl-pentan-1-olor 4-[3-(3,3-Dimethyl-4-oxo-butoxy)-propoxy]-2,2-dimethyl-butyric acid.20. A compound of the formula II:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein (a) R¹ and R² are independently CO₂H, CO₂(C₁₋C₆)alkyl,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, or benzyl; or R¹,R², and the carbon to which they are both attached are taken together toform a (C₃₋C₇)cycloalkyl group; (b) R¹¹ and R¹² are independently CO₂H,CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl; or R¹¹, R¹², and the carbon to which they are both attachedare taken together to form a (C₃₋C₇)cycloalkyl group; (c) n is aninteger ranging from 1 to 6; (d) each occurrence of m is independentlyan integer ranging from 0 to 4; (e) W¹ and W² are independently(C₁₋C₆)alkyl, CH₂OH, C(O)OH, CHO, OC(O)R³, C(O)OR³, SO₃H,

 where (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups; (iii) each occurrence of R⁵ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl.
 21. A compound offormula IIa:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein (a) R¹ and R² are OH, COOH, CHO, COOR⁷, SO₃H,

 where (I) R⁷ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁸ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups, (iii) each occurrence of R⁹ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; (b) R³ and R⁴ are CO₂H,CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl; (c) R⁵ and R⁶ are hydrogen, halogen, (C₁₋C₄)alkyl,(C₁₋C₄)alkoxy, (C6)aryloxy, CN, or NO₂, N(R⁵)₂ where R⁵ is H,(C₁₋C₄)alkyl, phenyl, or benzyl; (d) each occurrence of m isindependently an integer ranging from 1 to 5; (e) each occurrence of nis independently an integer ranging from 0 to 4; and (f) *¹ and *²represent independent chiral-carbon centers, wherein each center mayindependently be R or S.
 22. A compound as in claim 21 wherein *¹ is achiral-carbon center of the stereochemical configuration R orsubstantially R.
 23. A compound as in claim 21 wherein *¹ is achiral-center of the stereochemical configuration S or substantially S.24. A compound as in claim 21 wherein *² is a chiral-carbon center ofthe stereochemical configuration R or substantially R.
 25. A compound asin claim 21 wherein *² is a chiral-center of the stereochemicalconfiguration S or substantially S.
 26. A compound of the formula III:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixturethereof, wherein (a) each occurrence of Z is independently CH₂, CH═CH,or phenyl, where each occurrence of m is independently an integerranging from 1 to 5, but when Z is phenyl then its associated m is 1;(b) G is (CH₂)_(x), CH₂CH═CHCH₂, CH═CH, CH₂-phenyl-CH₂, or phenyl, wherex is an integer ranging from 1 to 4; (c) W¹ and W² are independentlyC(R¹)(R²)—(CH₂)_(n-)Y where n is an integer ranging from 0 to 4; (d) R¹and R² are independently CO₂H, CO₂(C₁₋C₆)alkyl, (C₁₋C₆)alkyl,(C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, or benzyl or R¹ and R² are bothH, or R¹, R, and the carbon to which they are both attached are takentogether to form a (C₃-C₇)cycloalkyl group; (e) Y is (C₁₋C₆)alkyl,(CH₂)_(n)OH, (CH₂)_(n)COOH, (CH₂)_(n)CHO, (CH₂)_(n)COOR³, SO₃H,

 where (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups, (iii) each occurrence of R⁵ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; and (f) each occurrenceof p is independently 2 or 3 where the broken line represents anoptional presence of one or more additional carbon-carbon bonds thatwhen present complete one or more carbon-carbon double bonds.
 27. Thecompound of claim 26, wherein W¹ and W² are independentC(R¹)(R²)—(CH₂)_(n)—Y groups, where n is an independent integer rangingfrom 0 to 4, and each occurrence of Y is independently OH, COOR⁴, orCOOH.
 28. The compound of claim 26, wherein p is
 0. 29. The compound ofclaim 26, wherein p is
 1. 30. A compound of the formula IIIa:

or a pharmaceutically acceptable salt, hydrate, solvate, clathratethereof, wherein (a) each occurrence of m is independently an integerranging from 1 to 5; (b) x is an integer ranging from 1 to 4; (c) W¹ andW² are independently C(R¹)(R²)—(CH₂)_(n-)Y;

(d) each occurrence of R¹ or R² is independently (C₁₋C₆)alkyl,(C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl, benzyl, or R¹, R¹, and thecarbon to which they are both attached are taken together to form a(C₃-C₇)cycloalkyl group; (e) Y is (C₁₋C₆)alkyl, OH, COOH, CHO, COOR³,SO₃H,

 where (I) R³ is (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, (C₂₋C₆)alkynyl, phenyl,or benzyl and is unsubstituted or substituted with one or more halo, OH,(C₁₋C₆)alkoxy, or phenyl groups, (ii) each occurrence of R⁴ isindependently H, (C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂-C₆)alkynyl and isunsubstituted or substituted with one or two halo, OH, C₁₋C₆ alkoxy, orphenyl groups, (iii) each occurrence of R⁵ is independently H,(C₁₋C₆)alkyl, (C₂₋C₆)alkenyl, or (C₂₋C₆)alkynyl; and (f) each occurrenceof p is independently 0 or
 1. 31. The compound of claim 30, wherein W¹and W² are independent C(R¹)(R²)—(CH₂)_(n-)Y groups, where n is aninteger from 0 to 4, and each occurrence of Y is independently OH,COOR³, or COOH.
 32. The compound of claim 30, wherein p is
 0. 33. Thecompound of claim 30, wherein p is
 1. 34. A pharmaceutical compositioncomprising a compound of claim 1, 9, 15, 18, 20, 21, 26, or 30 and apharmaceutically acceptable vehicle, excipient, or diluent.
 35. Apharmaceutical composition comprising the following compound:6-(5,5-Dimethyl-6-hydroxy-hexane-1-sulfinyl)-2,2-dimethyl-hexan-1-ol orpharmaceutically acceptable salts, hydrates, solvates, clathrates,enantiomers, diasteriomers, racemates, or mixtures of steroisomersthereof and a pharmaceutically acceptable vehicle, excipient, ordiluent.
 36. A method for treating or preventing a cardiovasculardisease in a patient, comprising administering to a patient in need ofsuch treatment or prevention a therapeutically effective amount of acompound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 37. A method fortreating or preventing a dyslipidemia in a patient, comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a compound of claim 1, 9, 15, 18,20, 21, 26, or
 30. 38. A method for treating or preventing adyslipoproteinemia in a patient, comprising administering to a patientin need of such treatment or prevention a therapeutically effectiveamount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 39. Amethod for treating or preventing a disorder of glucose metabolism in apatient, comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compound of claim1, 9, 15, 18, 20, 21, 26, or
 30. 40. A method for treating or preventingAlzheimer's Disease in a patient, comprising administering to a patientin need of such treatment or prevention a therapeutically effectiveamount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 41. Amethod for treating or preventing Syndrome X or Metabolic Syndrome in apatient, comprising administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compound of claim1, 9, 15, 18, 20, 21, 26, or
 30. 42. A method for treating or preventingsepticemia in a patient, comprising administering to a patient in needof such treatment or prevention a therapeutically effective amount of acompound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 43. A method fortreating or preventing a thrombotic disorder in a patient, comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a compound of claim 1, 9, 15, 18,20, 21, 26, or
 30. 44. A method for treating or preventing a peroxisomeproliferator activated receptor associated disorder in a patient,comprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compound of claim 1,9, 15, 18,20, 21, 26, or
 30. 45. A method for treating or preventingobesity in a patient, comprising administering to a patient in need ofsuch treatment or prevention a therapeutically effective amount of acompound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 46. A method fortreating or preventing pancreatitis in a patient, comprisingadministering to a patient in need of such treatment or prevention atherapeutically effective amount of a compound of claim 1, 9, 15, 18,20, 21, 26, or
 30. 47. A method for treating or preventing hypertensionin a patient, comprising administering to a patient in need of suchtreatment or prevention a therapeutically effective amount of a compoundof claim 1, 9, 15, 18, 20, 21, 26, or
 30. 48. A method for treating orpreventing renal disease in a patient, comprising administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.49. A method for treating or preventing cancer in a patient, comprisingadministering to a patient in claim 1, 9, 15, 18, 20, 21, 26, or
 30. 50.A method for treating or preventing inflammation in a patient,comprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compound of claim 1,9, 15, 18, 20, 21, 26, or
 30. 51. A method for treating or preventingimpotence in a patient, comprising administering to a patient in need ofsuch treatment or prevention a therapeutically effective amount of acompound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 52. A method fortreating or preventing a neurodegenerative disease or disorder in apatient, comprising administering to a patient in need of such treatmentor prevention a therapeutically or prophylactically effective amount ofa compound of claim 1, 9, 15, 18, 20, 21, 26, or
 30. 53. A method ofinhibiting hepatic fatty acid synthesis in a patient, comprisingadministering to a patient in need thereof a therapeutically orprophylactically effective amount of a compound of claim 1, 9, 15, 18,20, 21, 26, or
 30. 54. A method of inhibiting sterol synthesis in apatient, comprising administering to a patient in need thereof atherapeutically or prophylactically effective amount of a compound ofclaim 1, 9, 15, 18, 20,21, 26, or
 30. 55. A method of treating orpreventing metabolic syndrome disorders in a patient, comprisingadministering to a patient in need of such treatment or prevention atherapeutically or prophylactically effective amount of a compound ofclaim 1, 9, 15, 18, 20, 21, 26, or
 30. 56. A method of treating orpreventing a disease or disorder that is capable of being treated orprevented by increasing HDL levels, which comprises administering to apatient in need of such treatment or prevention a therapeuticallyeffective amount of a compound of claim 1, 9, 15, 18, 20, 21, 26, or 30.57. A method of treating or preventing a disease or disorder that iscapable of being treated or prevented by lowering LDL levels, whichcomprises administering to such patient in need of such treatment orprevention a therapeutically effective amount of a compound of claim 1,9, 15, 18, 20, 21, 26, or 30.